Argininosuccinate Lyase Deficiency Causes an Endothelial-Dependent Form of Hypertension

Am J Hum Genet. 2018 Aug 2;103(2):276-287. doi: 10.1016/j.ajhg.2018.07.008.


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.

Keywords: Mendelian forms of hypertension; angiogenesis; argininosuccinate lyase; argininosuccinic aciduria; endothelial cells; endothelial dysfunction; hypertension; induced pluripotent stem cells; nitric oxide; oxidative stress.

Publication types

  • Clinical Trial
  • Research Support, N.I.H., Extramural

MeSH terms

  • Adolescent
  • Animals
  • Argininosuccinate Lyase / genetics*
  • Argininosuccinic Aciduria / genetics*
  • Blood Pressure / genetics
  • Cells, Cultured
  • Child
  • Disease Models, Animal
  • Endothelial Cells / pathology*
  • Endothelium, Vascular / pathology
  • Female
  • Humans
  • Hypertension / genetics*
  • Male
  • Mice
  • Mice, Transgenic
  • Neovascularization, Pathologic / genetics
  • Nitric Oxide / genetics
  • Oxidative Stress / genetics
  • Urea Cycle Disorders, Inborn / genetics


  • Nitric Oxide
  • Argininosuccinate Lyase