Angiogenesis is a complex physiological process. In recent years, the immune regulation of angiogenesis has received increasing attention, and innate immune cells, which are centred on macrophages, are thought to play important roles in vascular neogenesis and development. Various innate immune cells can act on the vasculature through a variety of mechanisms, with commonalities as well as differences and synergistic effects, which are crucial for the progression of vascular lesions. In recent years, monotherapy with antiangiogenic drugs has encountered therapeutic bottlenecks because of the short-term effect of 'vascular normalization'. The combination treatment of antiangiogenic therapy and immunotherapy breaks the traditional treatment pattern. While it has a remarkable curative effect and survival benefits, it also faces many challenges. This review focuses on innate immune cells and mainly introduces the regulatory mechanisms of monocytes, macrophages, natural killer (NK) cells, dendritic cells (DCs) and neutrophils in vascular lesions. The purpose of this paper was to elucidate the underlying mechanisms of angiogenesis and development and the current research status of innate immune cells in regulating vascular lesions in different states. This review provides a theoretical basis for addressing aberrant angiogenesis in disease processes or finding new antiangiogenic immune targets in inflammation and tumor.

Adhesion molecules are proteins expressed at the surface of various cell types. Their main contribution to immunity is to allow the infiltration of immune cells in an inflamed site. In cancer, adhesion molecules have been shown to promote tumor dissemination favoring the development of metastasis. While adhesion molecule inhibition approaches were unsuccessful for cancer control, their importance for the generation of an immune response alone or in combination with immunotherapies has gained interest over the past years. Currently, the balance of adhesion molecules for tumor promotion/inhibition is unclear. Here we review the role of selectins, intercellular adhesion molecules (ICAM) and vascular cell adhesion molecules (VCAM) from the perspective of the dual contribution of adhesion molecules in tumor progression and immunity.

Postinfarction revascularization is critical for repairing the infarcted myocardium and for stopping disease progression. Considering the limitations of surgical intervention, engineered cardiac patches (ECPs) are more effective in establishing rich blood supply networks. For efficacy, ECPs should promote the formation of more mature blood vessels to improve microcirculatory dysfunction and mitigate hypoxia-induced apoptosis. Developing collateral circulation between infarcted myocardium and ECPs for restoring blood perfusion remains a challenge. Here, an ion-conductive composite ECPs (GMA@OSM) with powerful angiogenesis-promoting ability was constructed. Based on dual-effect intervention of oxygen and strontium, the developed ECPs can promote the formation of high-density circulating microvascular network at the infarcted myocardium. In addition, the GMA@OSM possesses effective reactive oxygen species-scavenging capacity and can facilitate electrophysiological repair of myocardium with ionic conductivity. In vitro and in vivo studies indicate that the multifunctional GMA@OSM ECPs form well-developed collateral circulation with infarcted myocardium to protect cardiomyocytes and improve cardiac function. Overall, this study highlights the potential of a multifunctional platform for developing collateral circulation, which can lead to an effective therapeutic strategy for repairing myocardial infarction.

The incidence and mortality rates of malignant tumors are increasing annually, with gliomas and brain metastases linked to a poor prognosis. Hyperbaric oxygen therapy is a promising treatment modality for both gliomas and brain metastases. It can alleviate tumor hypoxia and enhance radiosensitivity. When combined with other treatments for gliomas, this therapy has the potential to enhance survival rates. This review addresses the progress in research on the use of hyperbaric oxygen therapy combined with radiotherapy. For brain metastases, the combination of hyperbaric oxygen therapy and stereotactic radiosurgery is both feasible and advantagenous. This combination not only offers protection against radiation-induced brain injury but also supports the recovery of neurological and motor functions. The incidence of adverse reactions to hyperbaric oxygen therapy is relatively low, and it is safe and manageable. Future efforts should be made to investigate the mechanisms by which hyperbaric oxygen therapy combined with radiotherapy treats gliomas and brain metastases, optimize protection of the combined treatment against brain injury, minimizing adverse reactions, conducting multidisciplinary research and clinical trials, and training healthcare providers to facilitate broader clinical application.

Cancer-associated fibroblasts (CAFs) are a major component of the tumor microenvironment (TME) and play a crucial role in tumor progression. The biological properties of tumors, such as drug resistance, vascularization, immunosuppression, and metastasis are closely associated with CAFs. During tumor development, CAFs contribute to tumor progression by remodeling the extracellular matrix (ECM), inhibiting immune cell function, promoting angiogenesis, and facilitating tumor cell growth, invasion, and metastasis. Studies have shown that CAFs can promote endothelial cell proliferation by directly secreting cytokines such as vascular endothelial growth factor (VEGF) and fibroblast Growth Factor (FGF), as well as through exosomes. CAFs also secrete the chemokine stromal cell-derived factor 1 (SDF-1) to recruit endothelial progenitor cells (EPCs) into the peripheral blood and guide their migration to the tumor periphery. Additionally, CAFs can induce tumor cells to transform into "endothelial cells" that participate in vascular wall formation. However, the precise mechanisms remain to be further investigated. Due to their widespread presence in various solid tumors and their tumor-promoting function, CAFs are emerging as therapeutic targets. In this review, we summarize the specific mechanisms through which CAFs promote angiogenesis and outline current therapeutic strategies targeting CAF-induced vascularization, ongoing clinical trials targeting CAFs, and discuss potential future treatment approaches. We hope this will contribute to the advancement of CAF-targeted tumor treatment strategies.

Exosomes (Exos), extracellular vesicles of endosomal origin, are a promising therapeutic platform for tissue regeneration. In the current study, an exosome-capturing scaffold (ECS) was designed to attract and anchor exosomes via electrostatic adherence followed by lipophilic interactions. Our findings demonstrate that local enrichment of exosomes in the ECS implanted into critical mandibular defects could significantly accelerate endogenous bone regeneration by enhancing vascularization at the defect site. Notably, neutrophil (PMN)-derived exosomes (PMN-Exos) were identified as the predominant exosome subtype among all captured exosomes. During endogenous bone regeneration, PMN-Exos promoted endogenous vascularization primarily by stimulating the proliferation of endothelial progenitor cells (EPCs), which play a pivotal role in the vasculogenesis of new blood vessels. Mechanistically, vascularization involved PMN-Exo-derived miR455-3p, which promotes EPC proliferation by targeting the Smad4 pathway. In conclusion, this study offers an ECS with broad application prospects for enhancing tissue regeneration by accelerating vascularization. The elucidation of underlying mechanisms paves the way for developing novel strategies to regenerate various tissues and organs.

The continued rise in recurrence and mortality rates of cervical cancer suggests the need to find novel therapeutic targets. Previous studies suggest that TRIP4 acts as a transcription factor to regulate cervical carcinogenesis and progression. Our aim was to explore whether the key downstream genes of TRIP4 functions same as TRIP4 in promoting cervical cancer development. We analyzed and confirmed the downstream targets of TRIP4 by RNA sequencing in cervical cancer cells with TRIP4 knockdown. The expression correlation between TRIP4 and GATA2 and the effect of GATA2 on cervical cancer cell growth were determined respectively by Western Blot, Scratch, Spheroid, and MTT analyses. Pulldown and ChIP experiments were performed to analyze the binding of TRIP4 to the promoter of GATA2. The clinical significance of GATA2 and TRIP4 expression in cervical cancer patients was analyzed by tissue microarray staining. GATA2 was highly expressed in cervical cancer tissues. Knockdown of GATA2 inhibited the growth, metastasis and stemness of cervical cancer cells and sensitized cervical cancer cells to radiation therapy. The inhibitory effect of TRIP4 knockdown on cervical cancer cells was rescued by GATA2 overexpression. Furthermore, TRIP4 could bind to the specific GATA2 promoter region, thereby activating its transcription. Clinical tissue microarray analysis indicated that the expression of TRIP4 and GATA2 was positively correlated, and high expression of both predicted a poor prognosis in cervical cancer patients. Our study demonstrated that GATA2 functions as the key downstream target of TRIP4 to promote cervical cancer progression and effective intervention of TRIP4/GATA2 signaling is expected to be developed as potential cervical cancer therapeutic strategy.

Our study aims to explore the regulatory role and underlying mechanisms of Lysine-specific demethylase 1 (LSD1) in angiogenesis following myocardial infarction (MI).

We generated inducible cardiomyocyte-specific Lsd1 knockout (Lsd1-cKO) mice and established a MI model. The function of LSD1 in cardiac angiogenesis in MI mice was assessed through echocardiography, histopathological staining, and immunofluorescence analysis. In vitro, Lsd1 silencing in cardiomyocytes was achieved by transfecting small interfering RNA (siRNA), followed by hypoxic treatment to simulate the in vivo MI model. The above cardiomyocyte-conditioned medium was collected and used to treat endothelial cells to observe changes in endothelial function. Additionally, we employed Cleavage Under Targets and Tagmentation sequencing (CUT&Tag-seq) to investigate the potential mechanisms by which LSD1 exerts its effects.

We found that the absence of LSD1 protected against cardiac dysfunction and promoted angiogenesis in mice with MI. Lsd1-silenced cardiomyocytes enhance the migration and tube formation function of endothelial cells by releasing vascular endothelial growth factor A (VEGF-A) under hypoxic conditions. The combined analysis of CUT&Tag-seq data revealed that silencing of Lsd1 promoted the monomethylation of H3K4 at the Vegfa promoter and region, leading to the transcriptional activation of Vegfa mRNA in cardiomyocytes.

Our research indicates that lowered level of LSD1 in cardiomyocytes enhances VEGF-A paracrine secretion and improves endothelial cell function through cross-talk, ultimately promoting angiogenesis. These findings suggest that targeting LSD1 might be an effective therapeutic approach to protect against MI.

A developing tumor relies heavily on blood vessels to supply oxygen and nutrients. As a result, angiogenesis, the formation of new blood vessels, supports tumor growth and progression. Similarly, lymphangiogenesis, the formation of new lymphatic vessels, plays a critical role in metastatic dissemination by providing pathways for malignant cells to spread. The tumor microenvironment is crucial for establishing and maintaining these vascular networks, with innate immune cells playing a key regulatory role. Notably, immune cells are specifically enriched in barrier tissues, such as the skin, emphasizing their importance in skin malignancies. Therefore, understanding their role in regulating angiogenesis and lymphangiogenesis is essential for developing novel therapeutic strategies. This review article explores how innate immune cells influence tumor vasculature and highlights the therapeutic potential that may arise from this knowledge.

The blood-brain barrier constitutes a dynamic and interactive boundary separating the central nervous system and the peripheral circulation. It tightly modulates the ion transport and nutrient influx, while restricting the entry of harmful factors, and selectively limiting the migration of immune cells, thereby maintaining brain homeostasis. Despite the well-established association between blood-brain barrier disruption and most neurodegenerative/neuroinflammatory diseases, much remains unknown about the factors influencing its physiology and the mechanisms underlying its breakdown. Moreover, the role of blood-brain barrier breakdown in the translational failure underlying therapies for brain disorders is just starting to be understood. This review aims to revisit this concept of "blood-brain barrier breakdown," delving into the most controversial aspects, prevalent challenges, and knowledge gaps concerning the lack of blood-brain barrier integrity. By moving beyond the oversimplistic dichotomy of an "open"/"bad" or a "closed"/"good" barrier, our objective is to provide a more comprehensive insight into blood-brain barrier dynamics, to identify novel targets and/or therapeutic approaches aimed at mitigating blood-brain barrier dysfunction. Furthermore, in this review, we advocate for considering the diverse time- and location-dependent alterations in the blood-brain barrier, which go beyond tight-junction disruption or brain endothelial cell breakdown, illustrated through the dynamics of ischemic stroke as a case study. Through this exploration, we seek to underscore the complexity of blood-brain barrier dysfunction and its implications for the pathogenesis and therapy of brain diseases.

Gastric cancer (GC) is a malignant tumor with one of the highest morbidity and death rates in the world. Neoadjuvant therapy, including neoadjuvant chemotherapy (NAC) and NAC combined with immunotherapy, can improve the resection and long-term survival rates. However, not all patients respond well to neoadjuvant therapy. It has been confirmed that immune cells in the tumor immune microenvironment, including T cells, B cells, and natural killer cells, can affect the efficacy of neoadjuvant therapy. This paper summarizes current preclinical and clinical evidence to more fully describe the effects of neoadjuvant therapy on the immune microenvironment of GC, to provide the impetus to identify biomarkers to predict the potency of neoadjuvant therapy, and to identify the mechanisms of drug resistance, which should promote the development of individualized and accurate treatments for GC patients.

Dysregulated angiogenesis signaling leads to pathological vascular growth and leakage, and is a hallmark of many diseases including cancer and ocular diseases. In peripheral arterial disease, the concomitant increase in vascular permeability presents significant challenges in therapeutic efforts to improve perfusion by stimulating vascular growth. Building a mechanistic understanding of the endothelial control of vascular growth and permeability signaling is crucial to guide our efforts to identify therapeutic strategies that permit blood vessel growth while maintaining vascular stability. We develop a mechanistic systems biology model of the endothelial signaling network formed by the vascular endothelial growth factor (VEGF) and angiopoietin (Ang)-Tie pathways, two major signaling pathways regulating vascular growth and stability. Our model, calibrated and validated against experimental data, reveals the mechanisms through which chronic Ang1 stimulation protects endothelial cells from VEGF-induced hyperpermeability, and predicts that combining Src inhibition with Tie2 activation can inhibit vascular leakage without disturbing angiogenesis signaling.

ABSTRACT/SUMMARYAnti-angiogenics, inhibitors of pathological blood vessel growth, are an important class of targeted agent for the treatment of common cancers and ocular conditions. However, efficacy is compromised by the absence of biomarkers to guide patient selection or inform the management of resistance. We describe an assay for modified endothelial cell (EC) responses to the VEGF-A-neutralizing monoclonal antibody bevacizumab as part of a biomarker discovery program. ECs are transduced by lentivector expressing an experimental or non-silencing shRNA, each co-expressed with a different fluorescent protein. A 1:1 mixed cell population is then cultured with bevacizumab or control antibody under VEGF-A-dependent conditions. A normalized ratio of surviving cells, obtained by flow cytometry analysis, reflects EC resistance or sensitization to bevacizumab mediated by the experimental shRNA. With reagents prepared, the protocol takes 10 days and rigorously quantifies the impact of gene perturbation on the EC response to bevacizumab or other targeted anti-angiogenics.

Toll-like receptor 4 (TLR4), recognized as a fundamental mediator of inflammatory signaling, plays a crucial role in orchestrating the inflammatory response. Previous studies suggested that TLR4 knockout (KO) notably reduced corneal vascular areas induced by silver nitrate burn based on the morphological observation. The current study seeks to elucidate the influence of TLR4 signaling on corneal neovascularization (CNV) and to examine the underlying mechanisms. The model of alkali burn (AB)-induced CNV was built using TLR4 KO and wildtype (WT) mice. CNV was detected using a slit lamp. Corneal thickness was evaluated using H&E staining. The expression levels of VEGF-A, MyD88, and NF-κB were evaluated employing Western blot analysis, immunohistochemistry, and Real-time PCR techniques. The inflammation factors, IL-1β, TNF-α, and IL-6, were quantified using Real-time PCR. In addition, Resatorvid (Tak242), a specific inhibitor of TLR4, was used to treat AB cornea of WT mice. AB enhanced TLR4 signaling components, including MyD88 and NF-κB. TLR4 inhibition alleviated AB-induced corneal neovascularization and corneal thickness. The TLR4 signal, inflammatory factors and VEGF-A were also down-regulated. Our data indicated that TLR4 participated in the pathology of AB-induced CNV. TLR4 was over-expressed in the cornea of AB mice. TLR4 inhibition alleviated AB-induced CNV, and suppressed MyD88, NF-κB, VEGF-A, and inflammation factors. These findings may provide new insights for the clinical treatment of AB-induced CNV.

Recent studies have revealed that the malignant progression of hepatocellular carcinoma (HCC) not only stems from tumor cell-intrinsic genetic alterations but is dynamically regulated by the tumor microenvironment (TME). As a pivotal component of TME, tumor-associated endothelial cells (TECs) critically drive HCC progression through dual mechanisms of vascular abnormality and immune modulation. TECs establish a pro-tumorigenic niche by constructing disordered vascular networks while concurrently secreting immunosuppressive factors that induce immune cell dysfunction. This review systematically examines the molecular mechanisms underlying the dynamic transition from hepatic endothelial cells to TECs, identifies key TEC subtypes mediating tumor angiogenesis and immune evasion, and elucidates their crosstalk with immunosuppressive components. Additionally, we highlight TEC-specific biomarkers associated with clinical HCC progression and synthesize current clinical trials targeting TEC-mediated pathways. These findings provide novel insights for developing precision therapies that disrupt the TEC-TME-immune axis in HCC.

Pro-angiogenic therapy aims to stimulate the formation of new blood vessels, thereby enhancing blood flow to tissues and organs. Current strategies, such as growth factors, gene therapy, and cell-based approaches, are widely employed to promote angiogenesis. However, these interventions often suffer from off-target effects and limited efficacy due to the complex regulation of angiogenesis. Chinese herbal medicine (CHM) provides a rich source of therapeutic agents and offers promising alternatives for the treatment of vascular insufficiency-related disorders.

This review aims to summarise current research on the pro-angiogenic effects and underlying molecular mechanisms of CHM, including herbal extracts, traditional formulations and key bioactive phytochemicals.

A comprehensive literature search was conducted using electronic databases, including PubMed, Web of Science, and Google Scholar, covering publications from 2003 to 2024. Keywords including "Pro-angiogenic", "Angiogenesis", "Phytochemicals", "Traditional Chinese Medicine", "Natural compounds", "Phytomedicine", "Plant medicine", "Botanical drugs" and "Chinese herbal medicine" were used to retrieve relevant studies. The retrieved articles were then assessed, summarised. and synthesised to provide a comprehensive overview of the pro-angiogenic effects of CHMs and the molecular mechanisms underpinning these effects.

We systematically summarised the key molecular mechanisms involved in angiogenesis, including the vascular endothelial growth factor (VEGF), notch signalling, angiopoietin-tie, fibroblast growth factor, platelet-derived growth factor and hypoxia-inducible factor (HIF) pathways. Mechanistically, CHMs exert pro-angiogenic effects through promoting cell survival, proliferation, and migration, primarily through the upregulation of VEGF, Notch signalling, MAPK signalling, HIF-1α, and PI3K- Protein Kinase B (Akt) signalling pathways.

Multiple Chinese herbal extracts, formulations and key phytochemicals demonstrate significant pro-angiogenic effects. The mechanisms of these effects are multifaceted. The evidence highlights the potential of CHMs as promising candidates for pro-angiogenic therapy, warranting the need for further research and development to fully harness their therapeutic value.

Vascular organoids (VOs) are valuable tools for studying vascular development, disease, and regenerative medicine. However, controlling endothelial and mural compartments independently remains challenging. Here, we present a streamlined method to generate VOs from induced pluripotent stem cells (iPSCs) via orthogonal activation of the transcription factors (TFs) ETV2 and NKX3.1 using Dox-inducible or modRNA systems. This approach enables efficient co-differentiation of endothelial cells (iECs) and mural cells (iMCs), producing functional 3D VOs in 5 days without ECM embedding. VOs matured further upon ECM exposure, forming larger, structured vessels. Single-cell RNA sequencing revealed vascular heterogeneity, and temporal regulation of TF expression allowed modulation of arterial and angiogenic iEC phenotypes. In vivo, VOs engrafted into immunodeficient mice, formed perfused vasculature, and promoted revascularization in models of hind limb ischemia and pancreatic islet transplantation. These findings establish a rapid and versatile VO platform with broad potential for vascular modeling, disease studies, and regenerative cell therapy.

Stem cell therapy has demonstrated promise in regenerative medicine due to their ability to differentiate into various cell types and secrete growth factors. However, challenges such as poor survival rate of transplanted cells under ischemic and immune conditions limit its effectiveness. To address these issues, we developed a polycaprolactone (PCL)-fibrin-alginate matrix hydrogel, which combines adipose-derived stem cells and human umbilical vein endothelial cells with a PCL fiber, encapsulated within fibrin and alginate hydrogel to enhance cell survival, proliferation, and immune modulation. This structure offers protection to the encapsulated cells, supports angiogenesis, and modulates the immune response, significantly improving therapeutic outcomes in a mouse model of hindlimb ischemia. Our in vitro and in vivo results demonstrate the scaffold's ability to support cell viability, promote angiogenesis, and modulate inflammatory responses, indicating its potential as a promising platform for ischemic tissue repair and regenerative medicine. This innovative approach to cell-based therapy highlights the importance of scaffold design in enhancing the therapeutic efficacy of stem cell treatments for ischemic diseases.

Adaptive angiogenesis can drive repair or underlie the pathogenesis of tissue remodeling. Pulmonary vascular dysfunction is a major manifestation of chronic lung disease (CLD), but the role of angiogenesis in the development of CLD is not well defined. Microvascular capillaries in the alveolar-capillary network are the vessels most affected by pruning and remodeling in the lung, resulting in reduced capillary length and diameter with subsequent loss of gas exchange surfaces. Our lab has previously demonstrated that microvascular endothelial progenitor cells (mvEPCs) drive reparative angiogenesis. We hypothesize that visualization of the alveolar-capillary microvasculature in three-dimensions is essential to define the mechanisms governing repair versus progression to the pathogenesis of CLD. To address this gap in knowledge, we have developed a simple and reliable fluorescent perfusion technique that will allow the quantitation of microvessel structure in the alveolar-capillary network using mouse models of lung injury. This approach may be used in various organ systems to visualize microvasculature structure and its role in disease.NEW & NOTEWORTHY We developed and validated a fluorescent technology to visualize and quantify the alveolar-capillary network in three-dimensions in mouse lung for modeling of the microvasculature in models of lung disease.

Exosomes are small extracellular vesicles produced by most cell types and contain proteins, lipids, and nucleic acids (non-coding RNAs, mRNA, and DNA) that can be released by donor cells to influence the function of recipient cells. Skin photoaging is the premature aging of skin structures caused by prolonged exposure to ultraviolet (UV), as demonstrated by depigmentation, roughness, rhytides, elastosis, and precancerous alterations. Exosomes are associated with aging processes such as oxidative damage, inflammation, and senescence. Exosomes' anti-aging properties have been linked to various in vitro and preclinical investigations. There are still several unanswered questions about the use of MSC exosomes for skin rejuvenation, despite encouraging results. Uncertainty surrounds the precise processes by which exosomes stimulate the creation of collagen, skin tissue via a variety of mechanisms, including reduced matrix metalloproteinase (MMP) expression, increased collagen and elastin production, and modulation of intracellular signaling pathways and intercellular communication. These findings suggest the therapeutic potential of exosomes in skin aging. This review provides information on the molecular mechanisms and consequences of exosome anti-aging.

Traumatic brain injury (TBI) induces complex cellular and molecular changes, challenging recovery and therapeutic development. Although molecular pathways have been implicated in TBI pathology, the cellular specificity of these mechanisms remains underexplored. Here, we investigate the role of endothelial cell (EC) EphA4, a receptor tyrosine kinase receptor involved in axonal guidance, in modulating cell-specific transcriptomic changes within the damaged cerebral cortex. Utilizing single-cell RNA sequencing (scRNA-seq) in an experimental TBI model, we mapped transcriptional changes across various cell types, with a focus on astrocytes and ECs. Our analysis reveals that EC-specific knockout (KO) of EphA4 triggers significant alterations in astrocyte gene expression and shifts predominate subclusters. We identified six distinct astrocyte clusters (C0-C5) in the damaged cortex including as C0-Mobp/Plp1+; C1-Slc1a3/Clu+; C2-Hbb-bs/Hba-a1/Ndrg2+; C3-GFAP/Lcn2+; C4-Gli3/Mertk+, and C5-Cox8a+. We validate a new Sox9+ cluster expressing Mertk and Gas, which mediates efferocytosis to facilitate apoptotic cell clearance and anti-inflammatory responses. Transcriptomic and CellChat analyses of EC-KO cells highlights upregulation of neuroprotective pathways, including increased amyloid precursor protein (APP) and Gas6. Key pathways predicted to be modulated in astrocytes from EC-KO mice include oxidative phosphorylation and FOXO signaling, mitochondrial dysfunction and ephrin B signaling. Concurrently, metabolic and signaling pathways in endothelial cells-such as ceramide and sphingosine phosphate metabolism and NGF-stimulated transcription-indicate an adaptive response to a metabolically demanding post-injury hypoxic environment. These findings elucidate potential interplay between astrocytic and endothelial responses as well as transcriptional networks underlying cortical tissue damage.

Pancreatic cancer (PaCa) is a deadly malignancy that is often diagnosed at an advanced stage, limiting treatment and reducing survival. There is an urgent need for convenient and accurate diagnostic markers for the early detection of PaCa.

In this multicenter case-control study, we performed transcriptome analysis of 673 platelet samples from different in-house and public cohorts. RNA sequencing and RT-qPCR were used to discover and validate potential platelet biomarkers. A multi-gene signature was developed using binomial generalized linear model and independently validated in multicenter cohorts.

Two platelet RNAs, SCN1B and MAGOHB, consistently showed robust altered expression patterns between PaCa and healthy controls across cohorts, as confirmed by both RNA sequencing and RT-qPCR. The diagnostic two-RNA signature, PLA2Sig, demonstrated remarkable performance in detecting PaCa, with area under the receiver operating characteristic curve (AUC) values of 0.808, 0.900, 0.783, and 0.830 across multicenter cohorts. Furthermore, PLA2Sig effectively identified resectable stage I&II PaCa cases with an AUC of 0.812. Notably, PLA2Sig outperformed the traditional serum markers carcinoembryonic antigen and carbohydrate antigen 19-9 in distinguishing PaCa from healthy controls, and is complementary to established blood-based screening biomarkers.

These findings provide preliminary but promising evidence for the potential utility of platelet RNAs as an alternative non-invasive liquid biopsy tool for the early detection of PaCa.

Cerebral infarction (CI) is a common and frequently occurring acute neurological disease in clinical practice, posing a severe threat to human health. CI results from various causes leading to local cerebral tissue ischemia and hypoxia due to vascular occlusion and impaired blood supply, which in turn leads to tissue necrosis and corresponding clinical manifestations of neurological deficits. However, to date, treatment options for cerebral infarction remain limited. Therefore, it is crucial to rapidly establish collateral circulation to compensate for the occluded vessels and restore blood flow perfusion.

To assess the effect of bone marrow mesenchymal cells transfected with intelectin-1 (Itln-1) gene on the angiogenesis and apoptosis of CI.

Lentiviral-mediated transfection of the Itln-1 gene into bone marrow mesenchymal stem cells (BMSCs) was performed, followed by intravenous injection into rats with CI through the tail vein. The volume of the CI, capillary density, and apoptotic cells were detected.

With the increase of AKT and eNOS phosphorylation levels, BMSCs with overexpression Itln-1 gene could significantly promote angiogenesis and reduce the infarct volume in the ischemic penumbra. Meanwhile, the ratio of Bcl-2/Bax increased, and apoptotic cells decreased.

The overexpression of Itln-1 can effectively promote CI angiogenesis and inhibit cell apoptosis than transplantation of Itln-1 gene or MSCS alone.

Yak milk is a promising lipid source substitute for infant formulas designed to mimic human milk. However, comparative studies on the lipid profiles between human and yak milk are scarce. To address this gap, in this study, we thoroughly analysed and compared the lipidome and fatty acid (FA) composition of human colostrum, human mature milk and yak mature milk. A total of 2686 lipid species from 30 lipid classes were identified in the three milk types. Notably, yak mature milk surpassed both human milk stages in the total content of lipid species, triglycerides (TG) and saturated FA. In particular, three potential lipid biomarkers, namely TG(6,0_8,0_14:0) + NH4, TG(16,0_6,0_8:0) + NH4 and TG(10,0_12,0_12,0) + NH4, were identified to differentiate yak mature milk from human colostrum and mature milk. Moreover, upon analysing the lipid metabolic pathways, it was found that the lipids involved in the pathways of acetylcholine synthesis, as well as starch and sucrose metabolism, may not manifest notable differences between yak mature milk and human colostrum, indicating the presence of similar neurodevelopment-regulating and metabolic characteristics in yak milk as in colostrum. Therefore, this comprehensive comparison offers novel insights into the potential of yak mature milk lipids to enhance the humanisation of infant formulas.

This paper investigated the effects of three glycosides-astragaloside IV, amygdalin, and paeoniflorin (AAP)-derived from Buyang Huanwu Decoction combined with endothelial progenitor cell-derived exosomes (EPC-Exo), on vascular endothelial repair in rats following balloon-induced injury, with specific focus on the PI3K/AKT signaling pathway.

Endothelial progenitor cells (EPC) were isolated, cultured, and identified using immunofluorescence, with EPC-Exo being validated through Western blotting (WB), transmission electron microscopy, and particle size analysis. A rat model of endothelial injury was established using a HFD and carotid artery balloon injury (CABI). The rats were subsequently treated with AAP and/or EPC-Exo. Vascular repair was evaluated using hematoxylin-eosin (H&E) staining, ELISA, immunofluorescence, and WB. In vitro, endothelial cell injury was induced, and treatment effects were analyzed using CCK-8, scratch assays, tube formation assays, immunofluorescence, and WB. The involvement of the PI3K/AKT pathway was verified using the PI3K inhibitor LY294002.

The combination of AAP and EPC-Exo significantly reduced intimal hyperplasia, improved endothelial function, and promoted angiogenesis. Network pharmacology and molecular docking analyses demonstrated strong interactions between AAP and PI3K/AKT-related proteins. By enhancing the uptake of EPC-Exo by vascular endothelial cells (VEC), AAP promoted proliferation, migration, and tube formation in vitro while reducing Cleaved-caspase 3 expression. This combination also increased activation of the PI3K/AKT signaling pathway. The PI3K inhibitor weakened these effects, verifying the pathway's involvement in vascular repair.

The combination of AAP and EPC-Exo synergistically promotes vascular endothelial repair and angiogenesis, partly by enhancing EPC-Exo uptake through activation of the PI3K/AKT signaling pathway.

In recent years, various clinical trials have been designed and implemented using mesenchymal stem cells (MSCs) for the treatment of heart diseases. Clinical trials exploring MSC-based treatments have proliferated, yet the lack of standardized protocols for MSC administration remains a significant challenge. Despite the growing popularity of MSC trials, questions persist regarding optimal dosing, administration routes, and frequency to achieve safety and efficacy, particularly in the context of cardiac regeneration. The current study has reviewed the clinical trials that have used MSCs for the treatment of heart diseases since 2009. The findings reveal diverse transplantation methods and varying MSCs quantities, highlighting the absence of a universal guideline for MSCs utilization in heart disease clinical trials.

Diabetic skin, a major clinical challenge due to impaired wound healing, is often exacerbated by a hypoxic microenvironment at the wound site. Exosomes have been proven to have excellent biological activities and applied to solve many bioengineering problems. However, the wide application of exosomes is still limited by their short in vitro lifetime and low yield. To overcome these application limitations, this study specifically enhances the pro-angiogenic biological efficacy of exosomes through hypoxic treatment and achieves sustained release using hydrogel loading. In vitro, hypoxia-induced exosomes (Hp-Exo) significantly enhanced endothelial cell migration, proliferation, and angiogenic capacity. In vivo, Gelman hydrogels loaded with Hp-Exo accelerated wound closure, promoted collagen deposition, and increased vascularization in diabetic mice. miRNA sequencing of Hp-Exo revealed that exosomes induced under hypoxic conditions contain various miRNAs, which enhance vascular endothelial cell proliferation, migration, and angiogenesis through the PTEN/PI3K/AKT pathway. These results highlight that hypoxia-induced exosomes, when delivered through a biocompatible hydrogel platform, provide potential therapeutic approach to improve diabetic wound healing by stimulating angiogenesis and tissue regeneration.

Hepatocellular carcinoma (HCC) remains one of the most lethal cancers globally, driven by chronic liver disease and a complex tumor microenvironment (TME). Recent advances in spatial omics, single-cell analyses, and AI-driven digital pathology have shed light on the intricate heterogeneity of HCC, highlighting key roles for immune suppression, angiogenesis, and fibrosis in tumor progression. This review synthesizes current epidemiological trends, noting a shift from viral hepatitis to metabolic syndrome as a primary etiology in Western populations, and elucidates how TME components-such as tumor-associated macrophages, cancer-associated fibroblasts, vascular endothelial cells, and immunosuppressive cytokines-contribute to resistance against conventional therapies. We detail the evolution of immunotherapeutic strategies from monotherapy to combination regimens, including dual immune checkpoint blockade and the integration of antiangiogenic agents. Emerging circulating and tissue-based biomarkers offer promise for enhanced patient stratification and real-time monitoring of treatment responses. Collectively, these innovations herald a paradigm shift toward TME-directed precision oncology in HCC, emphasizing the need for multi-targeted approaches to synergistically modulate interacting cellular constituents and ultimately improve clinical outcomes.

This review aims to summarize the current applications of quantitative MRI biomarkers in the staging, treatment response evaluation, and prognostication of endometrial (EC) and cervical cancer (CC). By focusing on functional imaging techniques, we explore how these biomarkers enhance personalized cancer management beyond traditional morphological assessments.

A structured search of the PubMed database from January to May 2024 was conducted to identify relevant studies on quantitative MRI in uterine cancers. We included studies examining MRI biomarkers like Dynamic Contrast-Enhanced MRI (DCE-MRI), Diffusion-Weighted Imaging (DWI), and Magnetic Resonance Spectroscopy (MRS), emphasizing their roles in assessing tumor physiology, microstructure, and metabolic changes.

DCE-MRI provides valuable quantitative biomarkers such as Ktrans and Ve, which reflect microvascular characteristics and tumor aggressiveness, outperforming T2-weighted imaging in detecting critical factors like myometrial and cervical invasion. DWI, including advanced models like Intravoxel Incoherent Motion (IVIM), distinguishes between normal and cancerous tissue and correlates with tumor grade and treatment response. MRS identifies metabolic alterations, such as elevated choline and lipid signals, which serve as prognostic markers in uterine cancers.

Quantitative MRI offers a noninvasive method to assess key biomarkers that inform prognosis and guide treatment decisions in uterine cancers. By providing insights into tumor biology, these imaging techniques represent a significant step forward in the precision medicine era, allowing for a more tailored therapeutic approach based on the unique pathological and molecular characteristics of each tumor.

Biomarkers obtained from MRI can provide useful quantitative information about the nature of uterine cancers and their prognosis, both at diagnosis and response assessment, allowing better therapeutic strategies to be prepared.

Quantitative MRI improves diagnosis and management of uterine cancers through advanced imaging biomarkers. Quantitative MRI biomarkers enhance staging, prognosis, and treatment response assessment in uterine cancers. Quantitative MRI biomarkers support personalized treatment strategies and improve patient management in uterine cancers.

Successful immune checkpoint inhibitor (ICI) therapy occurs in only a fraction of melanoma patients, and yet all patients are susceptible to potentially serious ICI-related side-effects. No current biomarkers robustly predict ICI treatment response in melanoma patients. In this study we sought to identify methylome and transcriptome markers which have the potential to predict immunotherapy response in melanoma patients ahead of treatment with anti-PD1 ICI monotherapy. Using Infinium MethylationEPIC microarrays, we analysed DNA methylation profiles of >850,000 CpG sites in pre-treatment melanoma tissues from patients administered anti-PD-1 monotherapy as first-line treatment. In addition, we analysed transcriptomes using RNA-seq. DNA methylation and gene expression data were then statistically compared to patient response to anti-PD1 therapy. We identified 2579 DNA hypomethylation and hypermethylation alterations correlating with melanoma response to anti-PD1 therapy. An integrative analysis of DNA methylomes and transcriptomes identified a subset of 35 loci, 13 of which were significantly differentially methylated in both initial discovery and external validation datasets. Functional enrichment analysis of hypomethylated sites (p-value <0.05) in non-responders was associated with "Formation of the cornified envelope", "Regulation of epithelial cell proliferation", and "Purine-containing compound metabolic process". We have identified novel integrated DNA methylation and gene expression markers, which correlate with anti-PD1 treatment response in melanoma patients. These findings suggest a relationship between tumour-associated genomic DNA methylation, gene expression patterns, and anti-PD1 ICI immunotherapy response in melanoma patients.

Hypoxia is a critical factor affecting tissue homeostasis that dramatically alters the tumor microenvironment (TME) through genetic, metabolic, and structural changes, promoting tumor survival and proliferation. Hypoxia-inducible factor-1α (HIF-1α) plays a central role in this process by regulating hundreds of genes involved in the processes of tumorigenesis, angiogenesis, metabolic reprogramming, and immune evasion. This review provides a comprehensive examination of the role of HIF-1α in hypoxia and how hypoxia weakens intercellular junctions-including gap junctions, adherens junctions, tight junctions, and desmosomes. The disruption of gap junctions decreases intercellular communication, which alters signal transduction cascades and tumor suppressive properties. Adherens junctions are comprised of proteins that characterize the tissues and link cells to the actin cytoskeleton, whereby their disruption promotes the epithelial-to-mesenchymal transition (EMT). Under hypoxic conditions, the tight junction proteins are dysregulated, altering paracellular transport and cell polarity. In addition, desmosomes provide linkage to intermediate filaments, and hypoxia compromises tissue integrity. Collectively, the influence of hypoxia on cellular junctions promotes tumorigenesis through reducing cell communication, cytoskeletal interactions, and altering signaling pathways. Activation of matrix metalloproteinases (MMPs) further degrades the extracellular matrix and enhances tumor invasion and metastasis. This process also involves hypoxia-induced angiogenesis, regulated by HIF-1α. A comprehensive understanding of the mechanisms of hypoxia-driven tumor adaptation is essential for developing effective therapeutic strategies. Furthermore, this review examines current treatments aimed at targeting HIF-1α and explores future directions to enhance treatment efficacy and improve patient outcomes.

Alzheimer's Disease (AD) is characterized by complex brain alterations leading to progressive cognitive decline and neuropsychiatric disturbances. This narrative review explores these changes and the potential of diet and exercise as modifiable lifestyle factors to mitigate AD's impact. While some dietary components (e.g., B vitamins, ketogenic diet) and physical activity, particularly aerobic exercise, show promise for improving cognitive function and managing symptoms, evidence for consistent benefits remains limited and requires further investigation. Dietary and exercise research in AD faces significant limitations, including intervention complexity, study design challenges, disease heterogeneity, and difficulties in measuring long-term effects. Addressing these limitations is crucial to fully realize the therapeutic potential of these lifestyle interventions in combating AD.

The aging vasculature is characterized by endothelial dysfunction, arterial stiffness, and increased susceptibility to vascular pathologies. Central to these changes is the process of cellular senescence, where endothelial and vascular smooth muscle cells lose their replicative and functional capacity and adopt a pro-inflammatory secretory phenotype. This review provides an overview of the key mechanisms underlying vascular senescence, including the p53/p21 and p16/Rb pathways, the senescence-associated secretory phenotype (SASP), and oxidative stress, examines its contribution to cardiovascular diseases in older adults, and highlights emerging therapeutic strategies aimed at delaying or reversing these age-related vascular changes. In vascular cells, DNA damage, oxidative stress, and chronic inflammation associated with aging converge to amplify senescence. Clinically, vascular senescence is linked with hypertension, atherosclerosis, and increased overall cardiovascular risk. Several interventions, ranging from senolytics to lifestyle factors, show promise in mitigating these changes; however, long-term studies are needed. Given that vascular senescence is a pivotal driver of cardiovascular pathology in aging, targeting senescent cells or their secretory phenotype may potentially offer new avenues for preventing or attenuating age-related vascular diseases. This review presents an updated and integrative overview of vascular senescence, connecting fundamental cellular mechanisms with their clinical manifestations and highlighting the most promising therapeutic interventions.

Cell migration, which is often impaired under high glucose (HG) conditions, plays a crucial role in the pathogenesis of various diabetic complications. This study investigates the role of mitochondrial aldehyde dehydrogenase (ALDH2) in the HG-induced migratory inhibition. Using fibroblasts sub-cultured in HG medium as a cell model of chronic hyperglycemia, we found that prolonged exposure to HG stress inhibited cell migration via a novel mechanism independent of oxidative stress or cell death. By increasing osmolality, HG induced perinuclear clustering of mitochondria, enhanced focal adhesion maturation, and caused the cells to be less responsive to migratory cues. The pharmacological inhibition of ALDH2 exaggerated this phenomenon, while ALDH2 overexpression protected cells from the migratory impairment caused by HG-induced hyperosmolality. Cells with ALDH2 overexpression exhibited less mature focal adhesions and longer mitochondrial network, suggesting that ALDH2 might preserve mitochondrial integrity to facilitate the focal adhesion turnover during cell migration.

It has been demonstrated that glutamine is a key player in boosting endothelial cell (EC) proliferation. However, despite its importance, the role of endothelial glutaminolysis in diabetes remains largely unexplored. Our research aimed to investigate the function of glutaminolysis in ECs within the context of diabetes and to evaluate the potential therapeutic effects of salvianolic acid B (SalB) and α-ketoglutarate (α-KG) on diabetic vascular complications. Histological analysis of skin wounds in diabetic patients revealed delayed restoration of vascularization and collagen synthesis during wound healing, accompanied by decreased glutaminase 1 (GLS1) expression and reduced colocalization with the EC marker platelet-endothelial cell adhesion molecule-1 (CD31). Additionally, a significant decline in GLS1 activity and expression was observed in ECs isolated from diabetic hearts. In vitro studies using cultured ECs demonstrated that exposure to high glucose and high fat (HGHF) reduced GLS1 expression and suppressed glutaminolysis, impairing EC proliferation and tube formation. These adverse effects were mitigated by treatment with SalB or supplementation with α-KG plus nonessential amino acids (NEAAs). Among diabetic mice subjected to myocardial ischemia/reperfusion (MI/R), SalB administration or α-KG supplementation promoted myocardial revascularization and improved cardiac dysfunction. Notably, endothelial-specific GLS1 deletion in mice blocked the beneficial effects afforded by SalB but not those afforded by α-KG. Furthermore, SalB administration accelerated angiogenesis and cutaneous wound healing in diabetic mice, and these influences were removed by pharmacological inhibition of GLS1 using bis-2-(5-phenylacetamido-1,3,4-thiadiazol-2-yl) ethyl sulfide (BPTES) or genetic deletion of endothelial GLS1. These findings indicate that defective endothelial glutaminolysis contributes to impaired angiogenesis and poor ischemic tissue repair in diabetes. Improving endothelial glutaminolysis by treatment with SalB or metabolic supplementation with α-KG promotes angiogenesis and ischemic tissue repair in diabetic mice, emphasizing the possibility of GLS1 as a treatment target.

Glioblastoma (GBM) is one of the most aggressive primary brain tumors, characterized by extensive neovascularization and a highly infiltrative phenotype. Anti-vascular endothelial growth factor (VEGF) therapies, such as bevacizumab, have emerged as significant adjunct treatments for recurrent and high-grade GBM by targeting abnormal tumor vasculature. Despite demonstrated benefits in slowing tumor progression and alleviating peritumoral edema, these agents are associated with notable vascular complications, including hemorrhagic and ischemic events. Hemorrhagic complications range from minor intracranial microbleeds to life-threatening intracranial hemorrhages (ICH). Mechanistically, VEGF inhibition disrupts endothelial function and decreases vascular integrity, making already fragile tumor vessels prone to rupture. Glioma-associated vascular abnormalities, including disorganized vessel networks and compromised blood-brain barrier, further exacerbate bleeding risks. Concurrent use of anticoagulants, hypertension, and genetic predispositions also significantly elevate hemorrhagic risk. In addition to bleeding complications, ischemic events are increasingly recognized in patients receiving anti-VEGF therapy. Reduced vascular endothelial cells (ECs) survival and diminished microvascular density can lead to regional hypoperfusion and potentially precipitate cerebrovascular ischemia. Impaired vasoreactivity and increased vascular resistance, often accompanied by endothelial dysfunction and microvascular rarefaction, contribute to elevated stroke and arterial thrombotic risk. This review synthesizes current evidence on hemorrhagic and ischemic complications arising from anti-VEGF therapy in GBM. We discuss underlying pathophysiological mechanisms, risk factors, and clinically relevant biomarkers, as well as prevention strategies-such as rigorous blood pressure (BP) control and close monitoring of coagulation parameters. We further highlight emerging avenues in precision medicine, including pharmacogenomic profiling and targeted adjunct agents that protect vascular integrity, aimed at mitigating adverse vascular events while preserving therapeutic efficacy. The goal is to optimize outcomes for GBM patients by balancing the benefits of anti-VEGF therapy with vigilant management of its inherent vascular risks. In addition, this study analyzes existing clinical trials of the use of anti-VEGF drugs in the treatment of gliomas using data from the clinicaltirals.gov website.

Vascular endothelial growth factor (VEGF) signaling is a critical regulator of vasculogenesis, angiogenesis, and lymphangiogenesis, processes that are vital for the development of vascular and lymphatic systems, tissue repair, and the maintenance of homeostasis. VEGF ligands and their receptors orchestrate endothelial cell proliferation, migration, and survival, playing a pivotal role in dynamic vascular remodeling. Dysregulated VEGF signaling drives diverse pathological conditions, including tumor angiogenesis, cardiovascular diseases, and ocular disorders. Excessive VEGF activity promotes tumor growth, invasion, and metastasis, while insufficient signaling contributes to impaired wound healing and ischemic diseases. VEGF-targeted therapies, such as monoclonal antibodies and tyrosine kinase inhibitors, have revolutionized the treatment of diseases involving pathological angiogenesis, offering significant clinical benefits in oncology and ophthalmology. These therapies inhibit angiogenesis and slow disease progression, but they often face challenges such as therapeutic resistance, suboptimal efficacy, and adverse effects. To further explore these issues, this review provides a comprehensive overview of VEGF ligands and receptors, elucidating their molecular mechanisms and regulatory networks. It evaluates the latest progress in VEGF-targeted therapies and examines strategies to address current challenges, such as resistance mechanisms. Moreover, the discussion includes emerging therapeutic strategies such as innovative drug delivery systems and combination therapies, highlighting the continuous efforts to improve the effectiveness and safety of VEGF-targeted treatments. This review highlights the translational potential of recent discoveries in VEGF biology for improving patient outcomes.

This study aims to explore the molecules that affect the survival of Human Umbilical Vein Endothelial Cells (HUVECs) under hypoxia and their mechanisms of action. In hypoxia, plasmolipin (PLLP) was identified through the screening of CRISPR/Cas9 and small guide RNA (sgRNA) library. Functionally, PLLP knockout led to increase cell proliferation, cellular metabolism, tight junction formation, angiogenesis ability, migration and invasion in hypoxic HUVECs. Furthermore, PLLP knockout countered the inhibitory effects of bevacizumab on HUVECs angiogenesis and cell survival in hypoxic conditions. PLLP knockout was found to modulate the survival of HUVECs in hypoxia by enhancing the phosphorylation of AKT and ERK1/2 proteins. In conclusion, inhibiting the expression of PLLP in HUVECs promotes cell survival and maintenance of cellular functions under hypoxic condition. PLLP plays a crucial role in regulating cell survival in hypoxia through the activation of AKT and ERK1/2 pathways. This study identifies novel molecules that affect HUVECs survival under hypoxic conditions and provides a new possibility for future studies on cell survival under hypoxic conditions.

Kidney tumors are hypervascular tumors with crucial antiangiogenic effects in tumor therapy. This study aimed to develop a predictive model for kidney renal clear cell carcinoma (KIRC) by utilizing angiogenesis-related genes to formulate targeted therapy and immunotherapy strategies. Angiogenesis-related genes were screened via the GeneCard and Molecular Signatures Database (MSigDB). The KIRC data downloaded from The Cancer Genome Atlas (TCGA) were randomly divided into an experimental cohort and a validation cohort. In the experimental cohort, a risk score prediction model was constructed through successive analyses via univariate Cox regression, LASSO regression, and multivariate Cox regression. Receiver operating characteristic (ROC) curves were employed to assess the sensitivity of the model's predictions. The model's stability and generalizability were subsequently validated in both the validation cohort and the E-MTAB-1980 cohort. Subsequently, the TCGA-KIRC dataset was stratified into two distinct groups: a localized tumor cohort and a progression/metastasis cohort, based on tumor staging criteria. The efficacy of the prognostic prediction model was evaluated within each subgroup. A nomogram model was developed in conjunction with each independent prognostic factor to accurately predict patient outcomes. Additionally, single-cell and intercellular communication analyses were conducted via KIRC single-cell data obtained from the Gene Expression Omnibus (GEO) database. The effects of immunotherapy and targeted therapy on patients were predicted via prognostic modeling. A total of 260 angiogenesis-related genes were identified through screening in the GeneCards and Molecular Signatures Database(MSigDB). We subsequently developed a risk model comprising five genes: MEOX2, PLG, PROX1, TEK, and TIMP1. Survival analysis indicated that the prognosis for high-risk patients was significantly poorer than that for low-risk patients (P < 0.001), and the model demonstrated satisfactory accuracy in predicting 1-, 3-, and 5-year survival rates. This finding was further validated in both internal and external validation cohorts. The model demonstrated applicability for prognostic predictions in both the localized tumor cohort and the progression/metastasis cohort, with proficiency in forecasting the prognosis of patients diagnosed with metastatic renal cancer. The AUC values for 1, 3, and 5 years were recorded at 0.691, 0.709, and 0.773, respectively. We successfully constructed a nomogram model to facilitate accurate prognostic predictions for patients. Analysis of single-cell data revealed that PLG was expressed predominantly in tumor cell clusters, whereas TEK was highly expressed primarily in pericytes. TIMP1 was found to be highly expressed in vascular smooth muscle cells. In contrast, MEOX2 and PROX1 were highly expressed in specific cell clusters but presented low expression levels across the overall cell population. Cell communication analysis indicated that the modeling gene TEK was involved in the angiogenic pathway, with the interaction between the ligand ANGPT2 and the receptor ITGA5-ITGB1 being particularly prominent in this study. Furthermore, the immune dysfunction and rejection scores for high-risk patients within the non-localized renal cancer cohort were markedly elevated compared to those observed in the low-risk group. In terms of targeted pharmacological intervention, individuals classified in the low-risk group exhibited a heightened sensitivity to sorafenib. The KIRC prognostic prediction model, which is based on five angiogenesis-related genes, demonstrated reliable performance, indicating that high-risk patients have a significantly poorer prognosis than low-risk patients do. The developed nomogram model effectively visualizes and accurately predicts patient prognosis. It is essential to highlight that individuals diagnosed with low-risk metastatic KIRC may experience greater advantages from the administration of immunotherapy and sorafenib.