VEGF-A Stimulates STAT3 Activity via Nitrosylation of Myocardin to Regulate the Expression of Vascular Smooth Muscle Cell Differentiation Markers

Abstract

Vascular endothelial growth factor A (VEGF-A) is a pivotal player in angiogenesis. It is capable of influencing such cellular processes as tubulogenesis and vascular smooth muscle cell (VSMC) proliferation, yet very little is known about the actual signaling events that mediate VEGF-A induced VSMC phenotypic switch. In this report, we describe the identification of an intricate VEGF-A-induced signaling cascade that involves VEGFR2, STAT3, and Myocardin. We demonstrate that VEGF-A promotes VSMC proliferation via VEGFR2/STAT3-mediated upregulating the proliferation of markers like Cyclin D1 and PCNA. Specifically, VEGF-A leads to nitrosylation of Myocardin, weakens its effect on promoting the expression of contractile markers and is unable to inhibit the activation of STAT3. These observations reinforce the importance of nitric oxide and S-nitrosylation in angiogenesis and provide a mechanistic pathway for VEGF-A-induced VSMC phenotypic switch. In addition, Myocardin, GSNOR and GSNO can create a negative feedback loop to regulate the VSMC phenotypic switch. Thus, the discovery of this interactive network of signaling pathways provides novel and unexpected therapeutic targets for angiogenesis-dependent diseases.

LncRNA TNK2‐AS1 regulated ox‐LDL‐stimulated HASMC proliferation and migration via modulating VEGFA and FGF1 expression by sponging miR‐150‐5p

“…Among these predicted genes, we chose VEGFA and FGF1 for additional investigation. Previous studies have shown that VEGFA exerted enhanced effects on the VSMC proliferation as well as differentiation . In terms of FGF1, inhibition of FGF1 suppressed VSMC proliferation and migration, while overexpressed FGF1 in VSMCs exerted enhanced effects on cell proliferation and migration .…”

STAT3 in Skeletal Muscle Function and Disorders

“…STAT3 signaling has been shown to be activated in skeletal muscle and promotes skeletal muscle atrophy in muscle diseases, such as Duchenne muscular dystrophy (DMD), and Merosin-deficient congenital muscular dystrophy (MDC1A), as well as cancer and sepsis [ 7 , 8 , 9 ]. In addition to skeletal muscles, STAT3 signaling has been shown to play critical roles in both vascular and central nervous systems, thus directly and indirectly contributing to muscle health [ 10 , 11 , 12 , 13 ].…”

miRNA‐206 regulates human pulmonary microvascular endothelial cell apoptosis via targeting in chronic obstructive pulmonary disease

“…17 Notch3 is reported to play an important role in regulating the alveolar epithelium. 21,22 VEGFA inhibits cell apoptosis, stimulates endothelial cell migration and proliferation, and is widely expressed in highly vascularized organs such as lungs. 20 Vascular endothelial growth factor-A (VEGFA) is a potent multifunctional cytokine that has several effects on angiogenesis and is associated with COPD.…”

“…Importantly, Notch3 is identified as a target of miR‐206 in colorectal cancer cells, HeLa cells, and hepatocellular carcinoma cells . Vascular endothelial growth factor‐A (VEGFA) is a potent multifunctional cytokine that has several effects on angiogenesis and is associated with COPD . VEGFA inhibits cell apoptosis, stimulates endothelial cell migration and proliferation, and is widely expressed in highly vascularized organs such as lungs .…”