The hypoxic pulmonary vasoconstriction (HPV) response is unique to the pulmonary circulation. What is the MOST precisely understood molecular mechanism of HPV?
- A Low alveolar PO2 inhibits voltage-gated K⁺ channels (Kv) in pulmonary artery smooth muscle cells, causing membrane depolarization, L-type Ca²⁺ channel opening, Ca²⁺ influx, and contraction ✓
- B Hypoxia activates endothelial nitric oxide synthase, releasing NO that causes vasoconstriction paradoxically in the pulmonary vasculature
- C Hypoxia stimulates mast cell degranulation releasing histamine, which acts on H1 receptors on pulmonary arterial smooth muscle causing constriction
- D Hypoxia-inducible factor-1α (HIF-1α) activates endothelin-1 gene transcription, which then constricts pulmonary arterioles within seconds
Explanation
HPV occurs primarily in pulmonary arterial smooth muscle cells (PASMCs) in response to reduced alveolar (not arterial) PO2. Hypoxia inhibits oxygen-sensitive Kv channels (particularly Kv1.5, Kv2.1), reducing K⁺ efflux, depolarizing the membrane, and opening voltage-gated L-type Ca²⁺ channels. Ca²⁺ influx triggers myosin light chain kinase activation and smooth muscle contraction. This is the most extensively supported molecular mechanism. Additionally, hypoxia causes mitochondrial-generated reactive oxygen species that inhibit Kv channels. NO (option B) is vasodilatory in the pulmonary circulation; HPV is attenuated by NO. Option C (histamine from mast cells) is not the primary mechanism. Option D (HIF-1α/endothelin) is a long-term transcriptional response occurring over hours, not the acute HPV response.
Reference: Guyton & Hall, Textbook of Medical Physiology, 14th ed.
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