UBC Theses and Dissertations
The role of endothelial function in Marfan syndrome associated aortic root aneurysm : time to look beyond blood pressure control Yousefzadeh Tehrani, Arash
Marfan syndrome (MFS), a connective tissue disorder caused by mutations in the fibrillin-1 gene (FBN1), leads to progressive aortic root aneurysm. With no cure, MFS management relies on life-long use of blood pressure (BP)-lowering medications, mainly β-blockers or the angiotensin II (AngII) receptor type 1 (AT1R) blocker (ARB) losartan in an attempt to reduce aortic dilation rates and delay replacement surgery. However, despite many large-scale studies, conflicting clinical data have highlighted the underwhelming efficacy of BP-lowering-based pharmacotherapy at preventing aortic root widening, casting doubt on the therapeutic value of BP-lowering in MFS. In contrast, emerging evidence suggest the vascular endothelium and the nitric oxide (NO) system play a role in MFS aortic pathology and thus provide a novel therapeutic target for improving MFS management. Herein, using a mouse model of MFS, we demonstrate that BP-lowering with ARBs is of low therapeutic benefit to aortic root stability. The ARBs valsartan and losartan are both effective at attenuating aortic root widening and enhancing endothelial function despite valsartan being administered at a non-BP-lowering dose compared to losartan. Furthermore, telmisartan, an ARB most capable of enhancing endothelial function, can fully prevent MFS aortic root aneurysm through an endothelial NO synthase (eNOS)-dependent pathway, as in vivo inhibition of NOS activation renders telmisartan ineffective. Additionally, RNAseq data reveals smooth muscle cell genes potentially involved in the eNOS-dependent regulation of telmisartan’s effects on aortic remodeling. Lastly, we highlight ARB heterogeneity at activating endothelial function when administered at equivalent low BP-lowering doses. We show telmisartan to be the most potent activator of endothelial function among all clinically available ARBs and show this low-dose capable at attenuating MFs aortic root pathology further supporting endothelial function as the therapeutic driver behind ARBs’ anti-aortic remodeling effects. Overall, these studies establish the concept of achieving aortic root stability with ARBs in absence of BP-lowering and further identify eNOS-dependent activation of vascular endothelial function as a therapeutic driver of ARBs in MFS management. Moreover, these studies may aid in future MFS management guidelines with less focus on BP-lowering and more on endothelial function enhancement as well as guide future therapeutic development.
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