Mitochondrial arginase 2 regulates hematopoietic and cardiovascular adaptation to hypoxia Open Access

Mitochondrial arginase 2 regulates arginine availability, nitric oxide levels, and fatty acid metabolism.

Mitochondrial arginase 2 is a key regulator of hematopoietic and cardiovascular responses to acute and chronic hypoxia.

Physiological adaptation to hypoxia involves coordinated responses of the hematopoietic and cardiovascular systems to maintain tissue oxygenation. Arginine metabolism, via nitric oxide synthases and arginases, modulates both erythropoiesis and vascular tone. Arginase 2 (Arg2), a mitochondrial enzyme, may regulate these responses by limiting arginine availability for nitric oxide (NO) production. We hypothesized that deletion of Arg2 (Arg2KO) would augment NO bioavailability, attenuate hypoxia-driven hematopoiesis, and protect against pulmonary vascular remodeling. To test this, we exposed Arg2KO and wild-type (WT) mice to normoxia, short-term (6 – 72 hrs) or chronic (3 wks) hypoxia. In comparison to WT, Arg2KO mice under normoxia have fewer erythroid progenitors, comparable hematologic and cardiovascular parameters, but greater numbers of small vessels in the lungs. Under short-term hypoxia, Arg2KO mice have a blunted erythropoietic response with elevated plasma arginine and NO metabolites as compared to WT. Under chronic hypoxia, WT mice develop elevated right ventricular systolic pressure (RVSP) and remodeling of small pulmonary vessels. In contrast, Arg2KO do not increase RVSP or small vessel remodeling and maintain lower systemic blood pressure and heart rate compared to WT. Metabolically, endothelial cells from Arg2KO lungs demonstrate upregulation of arginine biosynthetic and fatty acid β-oxidation pathways, accompanied by less myocardial lipid droplet accumulation. These findings identify a previously unrecognized role for mitochondrial arginase 2 in regulating hematopoietic and vascular adaptation to hypoxia through modulation of nitric oxide signaling and metabolic reprogramming.