Vascular function in cavin‐1‐deficient mice: role of arginase 1 and dimethylarginine dimethylaminohydrolase 1

Abstract

Caveolae are invaginations in the plasma membrane important for normal cardiovascular function. Mice lacking caveolin‐1, a protein involved in caveolae biogenesis, show altered vascular function. Cavin‐1/PTRF is a recently identified protein critical for caveolae formation. Our aim was to investigate vascular function in mice deficient in cavin‐1. We found that cavin‐1 knock‐out (KO) mice have increased perinatal lethality. In mice that survived to adulthood we found remodeled blood vessels both in the periphery and in the lung. A microarray performed on lungs from newborn cavin‐1 KO mice showed altered expression enzymes involved in nitric oxide (NO) production, elevated Arginase1 (Arg1) and reduced dimethylarginine dimethylaminohydrolase 1 (DDAH1). In vitro studies in small arteries using myography show an enhanced relaxation to an Arg1 inhibitor (NOHA), confirming an increased enzyme activity in cavin‐1 KO mice. Decreases in DDAH1 have been shown to lead to pulmonary hypertension. We found that the decrease in DDAH1 expression was associated with an increased pressure in the right ventricle of the heart, suggesting a mild pulmonary hypertension in cavin‐1 KO mice. In spite of this, systemic blood pressure was normal. In conclusion, we find alterations in NO regulating enzymes that may be involved in limiting NO production in cavin‐1 deficient mice and resulting in mild pulmonary hypertension.