Smooth Muscle Cell-Specific Disruption of the BBSome Causes Vascular Dysfunction

Abstract

The BBSome, a complex consisting of 8 Bardet-Biedl syndrome (BBS) proteins, is involved in the regulation of various cellular processes. Recently, the BBSome complex has emerged as an important regulator of cardiovascular function with implications for disease. In this study, we examined the role of the BBSome in vascular smooth muscle and its effects on the regulation of cardiovascular function. Smooth muscle-specific disruption of the BBSome through tamoxifen-inducible deletion of Bbs1 gene, a critical component of the BBSome complex, reduces relaxation and enhances contractility of vascular rings and increases aortic stiffness independent of changes in arterial blood pressure. Mechanistically, we demonstrate that smooth muscle Bbs1 gene deletion increases vascular angiotensinogen gene expression implicating the renin-angiotensin system (RAS) in these altered cardiovascular responses. Additionally, we report that smooth muscle-specific Bbs1 knockout mice demonstrate enhanced endothelin-1 induced contractility of mesenteric arteries, an effect reversed by blockade of the angiotensin type 1 receptor with losartan. These findings highlight the importance of the smooth muscle BBSome in the control of vascular function and arterial stiffness through modulation of RAS signaling.

Summary

Smooth muscle-specific disruption of the BBSome causes vascular dysfunction and arterial stiffening. These vascular changes involve activation of the renin-angiotensin system as indicated by the increase in angiotensinogen gene expression and the ability of losartan to restores vascular function in mice lacking the BBSome in smooth muscle. Thus, the smooth muscle BBSome plays an important role in the regulation of vascular function and the development of arterial stiffness.