Smooth muscle α(v) integrins regulate vascular fibrosis via CD109 downregulation of TGF-β signalling

AIMS: α(v) integrins are implicated in fibrosis in a number of organs through their ability to activate TGF-β. However their role in vascular fibrosis and collagen accumulation is only partially understood. Here we have used α(v) conditional knockout mice and cell lines to determine how α(v) contributes to vascular smooth muscle cell (VSMC) function in vascular fibrosis and the role of TGF-β in that process. METHODS AND RESULTS: Angiotensin II (Ang II) treatment causes upregulation of α(v) and β(3) expression in the vessel wall, associated with increased collagen deposition. We found that deletion of α(v) integrin subunit from VSMCs (α(v)(SMKO)) protected mice against angiotensin II-induced collagen production and assembly. Transcriptomic analysis of the vessel wall in α(v)(SMKO) mice and controls identified a significant reduction in expression of fibrosis and related genes in α(v)(SMKO) mice. In contrast, α(v)(SMKO) mice showed prolonged expression of CD109, which is known to affect TGF-β signalling. Using cultured mouse and human VSMCs, we showed that overexpression of CD109 phenocopied knockdown of α(v) integrin, attenuating collagen expression, TGF-β activation, and Smad2/3 signalling in response to angiotensin II or TGF-β stimulation. CD109 and TGF-β receptor were internalized in early endosomes. CONCLUSION: We identify a role for VSMC α(v) integrin in vascular fibrosis and show that α(v) acts in concert with CD109 to regulate TGF-β signalling.