Loss Of Transforming Growth Factor Beta Signaling In Aortic Smooth Muscle Cells Causes Endothelial Dysfunction And Aortic Hypercontractility

Objective:Humans and mice with loss-of-function variants of genes in the TGF-beta (transforming growth factor beta) signaling pathway develop aortic aneurysms. These aneurysms could be caused by decreased aortic smooth muscle cell (SMC) contractile-protein levels and impaired aortic SMC contractile-unit function. Accordingly, we investigated whether loss of SMC TGF-beta signaling in mice alters aortic contractile-protein levels and aortic contractility.Approach and Results:We used immunoblotting, wire myography, histological analyses, and measurements of aortic nitric oxide and superoxide levels to assess aortic contractile-protein levels and vasomotor function in mice with SMC-specific deletion of the type 2 TGF-beta receptor (TBR2(SM Delta) mice). Aortic contractile-protein levels were not altered in TBR2(SM Delta) mice. Surprisingly, TBR2(SM Delta) mice had increased aortic contractility and severe endothelial dysfunction. Endothelial dysfunction was manifested as decreased relaxation to acetylcholine (Emax 37% versus 97%; P<0.0001), decreased aortic nitric oxide (50%; P=0.005), decreased endothelial nitric oxide synthase activation (31%; P=0.002), and lower aortic levels of phosphorylated vasodilator-stimulated phosphoprotein (an indicator of nitric oxide bioavailability: 65%; P<0.0001). Aortic hypercontractility was reduced by mechanical denudation of endothelium and was eliminated by pretreatment of TBR2(SM Delta) and control aortas with a nitric oxide synthase inhibitor, revealing a significant positive interaction between aortic hypercontractility and absence of endothelium-derived nitric oxide (P<0.05 for both denudation and nitric oxide inhibition).Conclusions:Aortic aneurysms that develop in TBR2(SM Delta) mice are not caused by decreased SMC contractility. Loss of physiological SMC TGF-beta signaling causes endothelial dysfunction leading to aortic hypercontractility. Endothelial dysfunction may contribute to vascular pathologies associated with abnormal TGF-beta signaling.