RhoA signaling and blood pressure: The consequence of failing to “Tone it Down”

Figure 1 Schematic summarizing RhoA-dependent regulation of vascular smooth muscle contraction and blood pressure homeostasis. Excitation-contraction coupling in smooth muscle cell (SMC) is mediated by the Ca²⁺-dependent activation of myosin light chain kinase (MLCK), and SMC tension is directly proportional to myosin light chain (MLC) phosphorylation (p) as this enables myosin’s molecular interaction with actin. SMC contractility is also regulated by GPCR-coupled contractile agonist-mediated activation of the small GTPase RhoA. Downstream activation of Rho kinase (ROCK) inhibits myosin phosphatase target subunit 1 (MYPT-1), and results in increased levels of pMLC to promote smooth muscle contraction. RhoA also stimulates G-actin polymerization to filamentous actin (F-actin). Actin polymerization increases SMC tension and stimulates myocardin-related transcription factor (MRTFs) nuclear translocation which promotes SRF-dependent transcription of contractile genes. RhoGAPs (such as GRAF3) and RhoGEFs dynamically regulate RhoA activity to achieve blood pressure balance.