Argininosuccinate lyase deficiency causes an endothelial-dependent form of hypertension. Homo sapiens

Nitric oxide (NO) is an important mediator of vascular homeostasis and its deficiency in murine models results in hypertension. However, there are few monogenic causes of NO deficiency in humans and the effects of such genetic forms of NO deficiency on vasculature are not well-studied. We have recently shown that argininosuccinate lyase (ASL), a urea cycle enzyme, is necessary for synthesis of NO. Deficiency of ASL leads to argininosuccinic aciduria, the second most common urea cycle disorder (UCD). In addition to hyperammonemia, the classic manifestation of UCDs, subjects with ASL deficieny can present with more complex clinical manifestations such as hypertension that is not typically observed in other UCDs. We hypothesized that loss of ASL in endothelial cells leads to altered vascular functions and is sufficient to cause hypertension.