Chronic hypoxia induces Rho kinase-dependent myogenic tone in small pulmonary arteries

Vascular Physiology Group, Department of Cell Biology and Physiology, University of New Mexico Health Sciences Center, Albuquerque, New Mexico Submitted 1 July 2007 ; accepted in final form 4 February 2008 Myogenic tone in the pulmonary vasculature of normoxic adult animals is minimal or nonexistent. Whereas chronic hypoxia (CH) increases basal tone in pulmonary arteries, it is unclear if a portion of this elevated tone is due to development of myogenicity. Since basal arterial RhoA activity and Rho kinase (ROK) expression are augmented by CH, we hypothesized that CH elicits myogenic reactivity in pulmonary arteries through ROK-dependent vascular smooth muscle (VSM) Ca 2+ sensitization. To test this hypothesis, we assessed the contribution of ROK to basal tone and pressure-induced vasoconstriction in endothelium-disrupted pulmonary arteries [50–300 µm inner diameter (ID)] from control and CH [4 wk at 0.5 atmosphere (atm)] rats. Arteries were loaded with fura-2 AM to continuously monitor VSM intracellular Ca 2+ concentration ([Ca 2+ ] i ). Basal VSM [Ca 2+ ] i was not different between groups. The ROK inhibitor, HA-1077 (100 nM to 30 µM), caused a concentration-dependent reduction of basal tone in CH arteries but had no effect in control vessels. In contrast, PKC inhibition with GF109203X (1 µM) did not alter basal tone. Furthermore, significant vasoconstriction in response to stepwise increases in intraluminal pressure (5–45 mmHg) was observed at 12, 15, 25, and 35 mmHg in arteries (50–200 µm ID) from CH rats. This myogenic reactivity was abolished by HA-1077 (10 µM) but not by GF109203X. VSM [Ca 2+ ] i was unaltered by HA-1077, GF109203X, or increases in pressure in either group. Myogenicity was not observed in larger vessels (200–300 µm ID). We conclude that CH induces myogenic tone in small pulmonary arteries through ROK-dependent myofilament Ca 2+ sensitization. pulmonary hypertension; protein kinase C; vascular smooth muscle; Ca 2+ sensitization; HA-1077 Address for reprint requests and other correspondence: T. C. Resta, Dept. of Cell Biology and Physiology, Univ. of New Mexico Health Sciences Center, MSC08 4750, 1 Univ. of New Mexico, Albuquerque, NM 87131-0001 (e-mail: tresta{at}salud.unm.edu )