Hypoxia responses in arginase 2 deficient mice enhance cardiovascular health

RATIONALE Physiological responses to hypoxia involve adaptations in the hematopoietic and cardiovascular systems, which work together to ensure adequate oxygen delivery to tissues for energy production. The arginine/nitric oxide (NO) pathway regulates both systems through its effects on erythropoiesis and vasodilation. In Tibetan populations native to high-altitude hypoxia, increased NO production from arginine and decreased arginine metabolism by arginase contribute to these adaptive mechanisms. These metabolic changes enhance tissue oxygen delivery and reduce the risk of hypoxic pulmonary hypertension. Here, we hypothesize that genetic deletion of mitochondrial arginase 2 ( Arg2 ) in mice will enhance cardiovascular effects and mitigate hypoxia-induced pulmonary hypertension. METHODS Complete blood counts, bone marrow erythroid differentiation, plasma arginine and NO (measured as nitrite), right ventricular systolic pressure (RVSP), heart rate, heart weight, and blood pressure were measured in wild-type (WT) and Arg2 knockout ( Arg2 KO) mice exposed to short-term (6, 12, 48, or 72 hours) or long-term (3 weeks) hypoxia. RESULTS Under normoxic conditions, Arg2 KO and WT mice exhibit similar RBC counts, hemoglobin levels, hematocrit, heart rate, systolic and diastolic blood pressures, and heart weight (all P > 0.05). WT mice increase erythropoiesis at 12 hours of hypoxia, including proerythroblasts (stage I, P = 0.004), polychromatic erythroblasts (stage III, P = 0.0004), and orthochromatic erythroblasts (stage IV, P = 0.03), but Arg2 KO mice do not increase erythropoiesis. After 48 hours of hypoxia, Arg2 KO mice increase proerythroblasts (stage I, P = 0.0008), but levels remain significantly lower than in WT mice. Plasma arginine and NO levels increase under hypoxia. NO levels peak at 12 hours of hypoxia in WT mice, then decline rapidly. In contrast, NO levels in Arg2 KO mice are higher than in WT mice, with sustained elevations at 48 hours of hypoxia ( P = 0.03). Arg2 KO mice have significantly higher plasma arginine levels than WT at 6, 12, and 72 hours of hypoxia (all P < 0.05). Under chronic hypoxia, Arg2 KO and WT mice show similar RBC counts, hemoglobin levels, hematocrit, and NO levels. Unlike WT, Arg2 KO mice do not increase RVSP ( P = 0.4) and have lower mean arterial ( P = 0.03) and diastolic blood pressures ( P = 0.01), as well as much lower heart rates ( P < 0.0001). Additionally, small blood vessels increase in lungs of Arg2 KO mice (CD31, P = 0.02; vWF, P = 0.6). CONCLUSIONS Arginine metabolism in the mitochondria plays a key role in modulating adaptive responses to hypoxia. Deletion of Arg2 results in delayed erythropoiesis under acute hypoxia, but better cardiovascular health, as indicated by higher levels of nitrite and arginine, and lower RVSP, blood pressure, and heart rate with chronic hypoxia.