%0 Journal Article
%T Argininosuccinate Lyase Deficiency Causes an Endothelial-Dependent Form of Hypertension
%A Anilkumar K. Reddy
%A Ayelet Erez
%A George G. Rodney
%A Hong Jiang
%A Jean J. Kim
%A Jordan Kho
%A Karl-Dimiter Bissig
%A Lindsay C. Burrage
%A Ming-Ming Jiang
%A Nathan S. Bryan
%A Oleg A. Shchelochkov
%A Ping Zhang
%A Reem Abo-Zahrah
%A Sandesh C.S. Nagamani
%A Shan Chen
%A Shuangtao Ma
%A Sridevi Devaraj
%A Terry Bertin
%A Wing-Tak Wong
%A Xiaoyu Tian
%A Zixue Jin
%J Archive of "American Journal of Human Genetics".
%D 2018
%R 10.1016/j.ajhg.2018.07.008
%X Primary hypertension is a major risk factor for ischemic heart disease, stroke, and chronic kidney disease. Insights obtained from the study of rare Mendelian forms of hypertension have been invaluable in elucidating the mechanisms causing primary hypertension and development of antihypertensive therapies. Endothelial cells play a key role in the regulation of blood pressure; however, a Mendelian form of hypertension that is primarily due to endothelial dysfunction has not yet been described. Here, we show that the urea cycle disorder, argininosuccinate lyase deficiency (ASLD), can manifest as a Mendelian form of endothelial-dependent hypertension. Using data from a human clinical study, a mouse model with endothelial-specific deletion of argininosuccinate lyase (Asl), and in vitro studies in human aortic endothelial cells and induced pluripotent stem cell-derived endothelial cells from individuals with ASLD, we show that loss of ASL in endothelial cells leads to endothelial-dependent vascular dysfunction with reduced nitric oxide (NO) production, increased oxidative stress, and impaired angiogenesis. Our findings show that ASLD is a unique model for studying NO-dependent endothelial dysfunction in human hypertension
%K argininosuccinate lyase
%K argininosuccinic aciduria
%K nitric oxide
%K hypertension
%K endothelial dysfunction
%K induced pluripotent stem cells
%K endothelial cells
%K Mendelian forms of hypertension
%K oxidative stress
%K angiogenesis
%U https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6080833/