Tuesday, May 7, 2024
5/7/2024
Project Summary Vascular smooth muscle cell (VSMC) phenotypic modulation, a phenotypic switch from a differentiated contractile phenotype to a proliferative phenotype, contributes to vascular remodeling and the development of diverse vascular diseases such as atherosclerosis, hypertension, and restenosis following angioplasty. However, the molecular mechanisms that control VSMC phenotypic modulation are poorly understood. Our exciting preliminary data strongly support a novel role of Runt-related transcription factor 3 (RUNX3) in VSMC phenotypic modulation. RUNX3 belongs to the ‘Runt domain’ family of transcription factors that act as regulators of gene expression in several important developmental pathways. We found that RUNX3 expression is significantly increased by platelet-derived growth factor-BB (PDGF-BB), a potent stimulator of VSMC phenotypic modulation. Knockdown of RUNX3 reversed PDGF-BB-inhibited expression of SMC contractile markers. In addition, RUNX3 knockdown blocked PDGF-BB-induced VSMC proliferation. These data demonstrate that RUNX3 is essential for PDGF-BB-induced VSMC phenotypic modulation and cell proliferation in vitro. In addition, RUNX3 overexpression blocked myocardin-induced a-SMA expression and promoter activity, suggesting that RUNX3 regulates VSMC contractile marker expression through myocardin/SRF signaling. RUNX3 knockdown also inhibited PDGF-BB induced expression of c-Myc, a crucial driver of VSMC proliferation. The PDGF-BB-induced activation of NF-¿B and phosphorylation of GSK3ß, important pathways in regulating c-Myc levels, were adversely affected by RUNX3 knockdown. RUNX3 expression was activated in the media and neointima VSMCs following the left common carotid artery injury in C57BL/6 mice. RUNX3 deficiency (RUNX3-/-) dramatically inhibited injury-induced neointima formation, suggesting that RUNX3 plays a critical role in injury-induced neointima formation and vascular remodeling in vivo. These data together strongly support a novel hypothesis that RUNX3 induces VSMC phenotypic modulation by suppressing VSMC contractile marker expression and promotes VSMC proliferation via c-Myc, leading to neointima formation/vascular remodeling, which will be tested by three Specific Aims. Aim 1: Determine the molecular mechanisms underlying RUNX3 function in modulating VSMC phenotype by testing the hypothesis that RUNX3 regulates VSMC phenotypic modulation via suppressing myocardin/SRF-mediated transcriptional activation of VSMC marker genes. Aim 2: Test the hypothesis that RUNX3 upregulates c-Myc expression through NF-¿B and GSK3ß/ß-catenin signaling to promote VSMC proliferation. Aim 3: Test whether RUNX3 is essential for carotid artery ligation/wire injury-induced vascular remodeling using global, VSMC-specific, and endothelial cell-specific RUNX3 knockout mice. Taken together, this project will shed new lights on the pathogenesis of vascular remodeling after vessel injury, which may ultimately lead to the identification of novel targets for therapeutic treatment of various cardiovascular diseases related to vascular remodeling.
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