Endothelial BBSome is essential for vascular, metabolic, and retinal functions

Abstract

Objectives: Endothelial cells that line the entire vascular system play a pivotal role in the control of various physiological processes, including metabolism. Additionally, endothelial dysfunction is associated with many pathological conditions, including obesity. Here, we assessed the role of the BBSome, a protein complex composed of eight Bardet-Biedl syndrome (BBS) proteins in endothelial cells. Methods: We studied the effects of BBSome disruption in endothelial cells on vascular function, body weight, glucose homeostasis, and the liver and retina. For this, we generated mice with selective BBSome disruption in endothelial cells through Bbs1 gene deletion. Results: We found that endothelial cell–specific BBSome disruption causes endothelial dysfunction, as indicated by the impaired acetylcholine-induced vasorelaxation in both the aorta and mesenteric artery. This was associated with an increase in the contractile response to thromboxane A2 receptor agonist (U46619) in the mesenteric artery. Mechanistically, we demonstrated that mice lacking the Bbs1 gene in endothelial cells show elevated vascular angiotensinogen gene expression, implicating renin-angiotensin system activation in the vascular changes evoked by endothelial BBSome deficiency. Strikingly, our data indicate that endothelial BBSome deficiency increases body weight and fat mass and causes hepatosteatosis along with alterations in hepatic expression of lipid metabolism–related genes and metabolomics profile. In addition, electroretinogram and optical coherence tomography analyses revealed functional and structural abnormalities in the retina, evoked by absence of the endothelial BBSome. Conclusions: Our findings demonstrate that the BBSome in endothelial cells is required for the regulation of vascular function, adiposity, hepatic lipid metabolism, and retinal function.

Keywords

• BBSome
• Endothelial function
• Body weight
• Liver steatosis
• Retina