The Role of Scleraxis in Inducing Vascular Stiffness

Abstract

Vascular fibrosis (VF) is one of the most significant pathologies related to blood vessel dysfunction. VF results in an impairment of vascular tone due to an increase in extracellular matrix proteins (ECM) and vascular smooth muscle synthesis within the vessel wall, thus increasing vascular stiffness and reducing lumen diameter. VF is both caused by and exacerbates numerous vascular diseases including diabetes, atherosclerosis and in particular, hypertension, which accounts for 13% of deaths globally (WHO World Health Report, 2002). Multiple studies have investigated various therapeutic approaches to interfere with VF, but to date this condition remains untreated, thus novel approaches to target fibrosis development and progression are urgently required.Our lab identified the transcription factor scleraxis as a novel master regulator of cellular phenotype conversion. We demonstrated that scleraxis is sufficient to induce fibroblast to myofibroblast phenotype conversion, a critical step in the development of fibrosis in many tissue types. Scleraxis also induces Epithelial to Mesenchymal Transition (EMT) and cell migration as part of development and cell differentiation. Some studies have shown that mechanical stretch in tendons increases expression of scleraxis, while additional studies reported that stretch in rabbit aorta induces the vascular smooth muscle proliferative phenotype. Our preliminary data has revealed that scleraxis is expressed in VSMCs in the arterial wall, and we have found elevated scleraxis expression in high pressure versus low pressure regions of vessels. We thus hypothesize that scleraxis is sufficient and necessary to induce vascular fibrosis.Our data shows that scleraxis overexpression increases thickness of the aortic vascular wall in scleraxis overexpression mice, via histological sections, thus contributing to the progression of vascular fibrosis. In vitro studies show that scleraxis overexpression in Human Aortic Smooth Muscle Cells (HAOSMC) induces their proliferation and migration using different assays (CCk8/Edu+ proliferation assay, Transwell migration assay, gene expression assays). Scleraxis overexpression also induces hypertrophy of HAOSMC shown via immunostaining. This suggests that scleraxis overexpression induces VSMC plasticity from contractile to synthetic‐proliferative phenotype, thus inducing VSMC hyperplasia.New & Noteworthy: Our findings indicate that scleraxis plays a role in VSMC plasticity via scleraxis‐ mediated transcriptional regulation of VSMC proliferation and migration. This work has potential relevance to many related diseases that feature VSMC activation, including atherosclerosis and restenosis.