Author:
Colman Laura,Caggiani Maria,Leyva Alejandro,Bresque Mariana,Liechocki Sally,Maya-Monteiro Clarissa M.,Mazal Daniel,Batthyany Carlos,Calliari Aldo,Contreras Paola,Escande Carlos
Abstract
AbstractCardiovascular diseases are among the main causes of morbimortality in the adult population. Among them, hypertension is a leading cause for stroke, heart disease and kidney failure. Also, as a result of arterial wall weakness, hypertension can lead to the development of dissecting aortic aneurysms, a rare but often fatal condition if not readily treated. In this work, we investigated the role of DBC1 in the regulation of vascular function in an ANGII-induced hypertension mouse model. We found that WT and DBC1 KO mice developed hypertension in response to ANGII infusion. However, DBC1 KO mice showed increased susceptibility to develop aortic dissections. The effect was accompanied by upregulation of vascular remodeling factors, including MMP9 and also VEGF. Consistent with this, we found decreased collagen deposition and elastic fiber fragmentation, suggesting that increased expression of MMPs in DBC1 KO mice weakens the arterial wall, promoting the formation of aortic dissections during treatment with ANGII. Finally, DBC1 KO mice had reduced cell proliferation in the intima-media layer in response to ANGII, paralleled with an impairment to increase wall thickness in response to hypertension. Furthermore, VSMC purified from DBC1 KO mice showed impaired capacity to leave quiescence, confirming the in vivo results. Altogether, our results show for the first time that DBC1 regulates vascular response and function during hypertension and protects against vascular injury. This work also brings novel insights into the molecular mechanisms of the development of aortic dissections.
Publisher
Springer Science and Business Media LLC
Reference65 articles.
1. O’Rourke, K., VanderZanden, A., Shepard, D. & Leach-Kemon, K. Cardiovascular disease worldwide, 1990-2013. Jama 314, 1905-1905 (2015).
2. Spittell, J. A. Hypertension and arterial aneurysm. Journal of the American College of Cardiology 1, 533–540 (1983).
3. Gawinecka, J., Schönrath, F. & von Eckardstein, A. Acute aortic dissection: pathogenesis, risk factors and diagnosis. Swiss medical weekly 147, w14489 (2017).
4. Forrester, S. J. et al. Angiotensin II signal transduction: an update on mechanisms of physiology and pathophysiology. Physiological reviews 98, 1627–1738 (2018).
5. Lerman, L. O. et al. Animal models of hypertension: a scientific statement from the American Heart Association. Hypertension 73, e87–e120 (2019).
Cited by
7 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献