Endothelial cells and blood vessels are major targets for COVID-19-induced tissue injury and spreading to various organs

Table 1 COVID-19 and endothelium/blood vessels

COVID-19 and endothelium/blood vessels
Endothelium and blood vessels are integral parts of COVID-19-induced tissue injury. Their injury is likely due to either direct viral infection and/or cytokine storm triggered by infection of adjacent epithelial cells and inflammatory response[18].
Blood vessels are critical for virus dissemination to distant organs.
Preexisting-impaired endothelial function, e.g., in aging or diabetes are likely predisposing factors COVID-19. Our studies demonstrated that aging gastric mucosa has increased susceptibility to injury and prominent EC abnormalities (decreased VEGF, NGF and impaired mitochondrial function)[19-21].
ECs are critical for vascular regeneration (through angiogenesis and vasculogenesis) during injury/lesions healing and therefore are essential for the delivery of oxygen and nutrients to the healing site[22, 23].
Several growth factors e.g., NGF, IGF-1, HGF and BMD-stem cells may facilitate tissue regeneration in the healing phase[20,24,25].
Long-term effects of COVID-19, its vaccines and treatment on endothelium and vasculature remain to be determined.
Recently, new oral drugs inhibiting viral replication–Molnupiravir (Merck) and Paxlovid (Pfizer) showed significant efficacy in controlling severe COVID-19 infection by inhibiting viral replication. The interim analysis of the latter drug showed an 89% reduction in risk of COVID-19-related hospitalization or death from any cause compared to placebo in patients treated within three-five days of symptom onset[26].

COVID-19: Coronavirus disease 2019; EC: Endothelial cell; VEGF: Vascular endothelial growth factor; NGF: Nerve growth factor.

Table 2 Scenarios by which SARS-CoV-2 elicits endothelial damage

Scenario A: SARS-CoV-2 infection	Scenario B: Cytokine storm
SARS-CoV-2 infects and replicates within vascular ECs and new virus particles are released into the blood vessel. These virions can infect neighboring cells or are carried to distant organs via circulation	↑ IL-6, IL-1β, and TNFα release (cytokine storm) → endothelial damage
	↑ vascular permeability → plasma extravasation
	↑ vWF & FVIII (promote clot formation) and ↑ PAI-1 (inhibits clots lysis) → hypercoagulation

SARS-CoV-2: Severe acute respiratory syndrome coronavirus 2; IL: Interleukin; TNF: Tumor necrosis factor; vWF: von Willebrand factor.

Table 3 Summary of the investigational interventions/treatments for COVID-19 in clinical trials

Intervention/ Treatment	Mode of action	Dose	Route	ClinicalTrials.gov Identifier
Ronapreve/REGN-COV2 (REGN10933 and REGN10987)	Monoclonal antibodies against spike proteins	8 g once, or 4 g twice	IV	NCT04425629
Lopinavir/Ritonavir	Inhibitor of the HIV protease and cytochrome P-450 CYP3A	200/ 50 mg; (4 tablets twice a day on day 1 followed by 2 tablets twice a day for 9 d)	Oral	NCT04403100
Remdesivir (RDV, GS-5734, Veklury)	Inhibitor of RNA-dependent RNA polymerase	200 mg on day 1 followed by 100 mg for 4-9 d	IV	NCT04292899
Hyperimmune Plasma (COV19-PLASMA)	Immunotherapy	250-300 mL up to 3 times over 5 d	IV	NCT04321421
Tocilizumab (TCZ, ROACTEMRA)	Humanized anti-IL6 receptor monoclonal antibody	8 mg/kg single infusion, up to 800 mg	IV	NCT04320615
Sarilumab (Kevzara, REGN88, SAR153191)	Monoclonal antibody against IL-6 receptor alpha	200 mg or 400 mg; single dose and multiple doses	IV	NCT04315298
Anakinra (KINERET)	Monoclonal antibody against the IL-1 receptor	100 mg daily up to 28 d	SC	NCT04330638
Siltuximab (SYLVANT)	Chimeric anti-IL-6 antibody	11 mg/kg single infusion	IV	NCT04330638
Eculizumab	Monoclonal antibody against complement protein C5	900 mg every 7 d	IV	NCT04288713
Methyl-prednisolone (MP)	Immunosuppression against cytokine storm	80 mg/kg IV bolus, followed by infusion of 80 mg/d for at least 8 d and then oral MP 16 mg or 20 mg IV twice daily	Oral-IV	NCT04323592
Heparin	Antithrombotic agents	10 units/kg/h	IV	NCT04367831
Enoxaparin (Lovenox)	Antithrombotic agents	1 mg/kg	SC	NCT04367831
Dexamethasone	Immunosuppression against cytokine storm	20 mg/d (5 d) then 10 mg/d (5 d)	IV	NCT04325061
Vitamin C	Antioxidant	12 g infusion twice a day for 7 d	IV	NCT04264533
Melatonin	Antioxidant	3 or 30 mg three times a day for 14 d	Oral	NCT04784754
CoQ10	Antioxidant	500 mg/day for 6 wk	Oral	NCT04960215

IL: Interleukin.