Hypoxic pulmonary vasoconstriction requires connexin 40–mediated endothelial signal conduction

Abstract

Hypoxic pulmonary vasoconstriction (HPV) is a physiological mechanism by which pulmonary arteries constrict in hypoxic lung areas in order to redirect blood flow to areas with greater oxygen supply. Both oxygen sensing and the contractile response are thought to be intrinsic to pulmonary arterial smooth muscle cells. Here we speculated that the ideal site for oxygen sensing might instead be at the alveolocapillary level, with subsequent retrograde propagation to upstream arterioles via connexin 40 (Cx40) endothelial gap junctions. HPV was largely attenuated by Cx40-specific and nonspecific gap junction uncouplers in the lungs of wildtype mice and in lungs from mice lacking Cx40 (Cx40 -/-). In vivo, hypoxemia was more severe in Cx40 -/-mice than in wild-type mice. Real-time fluorescence imaging revealed that hypoxia caused endothelial membrane depolarization in alveolar capillaries that propagated to upstream arterioles in wild-type, but not Cx40 -/-, mice. Transformation of endothelial depolarization into vasoconstriction involved endothelial voltage-dependent α 1G subtype Ca 2+ channels, cytosolic phospholipase A 2 , and epoxyeicosatrienoic acids. Based on these data, we propose that HPV originates at the alveolocapillary level, from which the hypoxic signal is propagated as endothelial membrane depolarization to upstream arterioles in a Cx40-dependent manner. IntroductionHypoxic pulmonary vasoconstriction (HPV) is a fundamental physiological mechanism by which the lung optimizes ventilation/ perfusion (V/Q) matching, redirecting blood flow from poorly to better ventilated areas (1). Yet in cases of global hypoxia, HPV may unfavorably increase total pulmonary vascular resistance and right ventricular afterload, thus contributing to the clinical pathology of pulmonary hypertension and cor pulmonale in chronic hypoxic lung diseases or to pulmonary edema at high altitude (1, 2). While the relevance of HPV has been recognized for over 60 years, the underlying oxygen sensing and signal transduction processes remain a topic of intense research and controversy. Current concepts of HPV are largely based on the notion that pulmonary arterial smooth muscle cells (PASMCs) constitute both the sensor and the transducer of the hypoxic signal as well as its contractile effector (1), while the role of the vascular endothelium is at best considered that of a modulating bystander.From a conceptual standpoint, the ideal site for an oxygen sensor in HPV is within the actual area of pulmonary gas exchange,

Endocannabinoid anandamide mediates hypoxic pulmonary vasoconstriction

“…These findings are in accordance with earlier studies, where AA and AAdependent eicosanoids were shown to modulate pulmonary tone and contribute to HPV (15,23,24) and pulmonary hypertension (16,25). A recent study suggests that pulmonary endothelial cytosolic phospholipase A2 generates AA and CYP450-dependent metabolites under hypoxia, resulting in vasoconstriction (26). Our data further extend this concept illustrating that hypoxia can also increase levels of an important precursor of vasoconstrictive eicosanoids and arachidonic acid in PASMCs.…”

Pulmonary Hypertension after Prolonged Hypoxic Exposure in Mice with a Congenital Deficiency of Cyp2j

“…The CYP epoxygenases Cyp2c and Cyp2j catalyze the formation of epoxyeicosatrienoic acids (EETs), which have antiinflammatory properties and are associated with vasodilation of the systemic circulation (6,7). In the pulmonary vasculature, EETs cause vasoconstriction (8) and are involved in the regulation of hypoxic pulmonary vasoconstriction (HPV) (6,9) and the PH associated with prolonged exposure to hypoxia (2,3). EETs are converted to their corresponding diols (dihydroxyeicosatrienoic acids [DHETs]) by soluble epoxide hydrolase (sEH) (10).…”

High-Altitude Pulmonary Vascular Diseases

“…This mechanism, termed hypoxic pulmonary vasoconstriction (HPV), is mainly mediated by endothelial and smooth muscle cells of small pulmonary arteries and veins, and perhaps the capillary endothelium itself. 6 Importantly, red cells, the autonomic nervous system, acid-base status, and numerous circulating and locally produced vasoactive substances further influence HPV in vivo. 7 It occurs even with modest reductions in alveolar PO 2 such as appears with decreases in F I O 2 to 0.15-0.18 or ascent above 5000 feet.…”