Hypoxic vasoconstriction of rat skeletal artery mediated by NOX4 and NOS/sGC pathway

Abstract

Deep femoral arteries (DFA) of rats show hypoxic (3% PO2) vasoconstriction (HVC), which required a pretone by α‐adrenergic (PhE) stimulation. Nifedipine completely abolished HVC. HVC appeared to be endothelium‐independent. However, both NO synthase (NOS) inhibitor (L‐NAME) and soluble guanylate cyclase (sGC) inhibitor (ODQ) largely augmented the PhE‐induced contraction of DFA, upon which no further HVC was elicited. Upon the PhE‐induced pretone, strong contraction was induced by NOX4 inhibitor (DPI or plumbagin), and additional hypoxia induced relaxation instead of HVC. Pretreatment with NOX2 inhibitor (apocynin) or with ROS scavengers did not inhibit HVC. The inhibitors of mitochondrial electron transport chain (rotenone, antimycin A, NaCN) or uncoupler (CCCP) suppressed HVC as well as the PhE‐induced pretone, indicating a general inhibition of contractility. Also, RhoA‐dependent kinase inhibitors (Y27632 and fasudil) suppressed HVC along with the inhibition of pretone. Taken together, it is suggested that NOX4 might play a critical early step for the HVC; NOX4‐dependent hypoxic inhibition of NOS/sGC might have augmented the PhE‐induced contraction of DFA. The HVC of skeletal arteries might have a physiological implication for matching the imbalance between the cardiac output and the skeletal blood flow under severe exercise or emergent hypoxia combined with increased sympathetic tone. This study was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (NRF 2011‐0017379 and 2011‐0001175).