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

AIMS

α 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 conditional knockout mice and cell lines to determine how α 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 and β expression in the vessel wall, associated with increased collagen deposition. We found that deletion of α integrin subunit from VSMCs (α ) protected mice against angiotensin II-induced collagen production and assembly. Transcriptomic analysis of the vessel wall in α mice and controls identified a significant reduction in expression of fibrosis and related genes in α mice. In contrast, α 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 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 integrin in vascular fibrosis and show that α acts in concert with CD109 to regulate TGF-β signalling.