Smooth muscle α_v integrins regulate vascular fibrosis via CD109 downregulation of TGF-β signalling

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.

Angiotensin II (Ang II) treatment causes upregulation of α_v and β₃ 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.

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.