It has been known for more than 60 years, and suspected for over 100, that alveolar hypoxia causes pulmonary vasoconstriction by means of mechanisms local to the lung. For the last 20 years, it has been clear that the essential sensor, transduction, and effector mechanisms responsible for hypoxic pulmonary vasoconstriction (HPV) reside in the pulmonary arterial smooth muscle cell. The main focus of this review is the cellular and molecular work performed to clarify these intrinsic mechanisms and to determine how they are facilitated and inhibited by the extrinsic influences of other cells. Because the interaction of intrinsic and extrinsic mechanisms is likely to shape expression of HPV in vivo, we relate results obtained in cells to HPV in more intact preparations, such as intact and isolated lungs and isolated pulmonary vessels. Finally, we evaluate evidence regarding the contribution of HPV to the physiological and pathophysiological processes involved in the transition from fetal to neonatal life, pulmonary gas exchange, high-altitude pulmonary edema, and pulmonary hypertension. Although understanding of HPV has advanced significantly, major areas of ignorance and uncertainty await resolution.

Chronic hypoxia induces polycythemia, pulmonary hypertension, right ventricular hypertrophy, and weight loss. Hypoxia-inducible factor 1 (HIF-1) activates transcription of genes encoding proteins that mediate adaptive responses to hypoxia, including erythropoietin, vascular endothelial growth factor, and glycolytic enzymes. Expression of the HIF-1α subunit increases exponentially as O 2 concentration is decreased. Hif1a -/-mouse embryos with complete deficiency of HIF-1α due to homozygosity for a null allele at the Hif1a locus die at midgestation, with multiple cardiovascular malformations and mesenchymal cell death. Hif1a +/-heterozygotes develop normally and are indistinguishable from Hif1a +/+ wild-type littermates when maintained under normoxic conditions. In this study, the physiological responses of Hif1a +/-and Hif1a +/+ mice exposed to 10% O 2 for one to six weeks were analyzed. Hif1a +/-mice demonstrated significantly delayed development of polycythemia, right ventricular hypertrophy, pulmonary hypertension, and pulmonary vascular remodeling and significantly greater weight loss compared with wild-type littermates. These results indicate that partial HIF-1α deficiency has significant effects on multiple systemic responses to chronic hypoxia.

Abstract-Chronic hypoxia (CH) causes pulmonary vasoconstriction because of increased pulmonary arterial smooth muscle cell (PASMC) contraction and proliferation. We previously demonstrated that intracellular Ca 2ϩ concentration ([Ca 2ϩ ] i ) was elevated in PASMCs from chronically hypoxic rats because of Ca 2ϩ influx through pathways other than L-type Ca 2ϩ channels and that development of hypoxic pulmonary hypertension required full expression of the transcription factor hypoxia inducible factor 1 (HIF-1). In this study, we examined the effect of CH on the activity and expression of store-operated Ca 2ϩ channels (SOCCs) and the regulation of these channels by HIF- Key Words: Ca 2ϩ channels Ⅲ hypoxia Ⅲ hypoxia-inducible factor 1 Ⅲ hypoxic pulmonary vasoconstriction Ⅲ vascular smooth muscle P rolonged exposure to alveolar hypoxia is associated with changes in the pulmonary vasculature including structural remodeling 1,2 and active contraction of vascular smooth muscle. 3,4 Recent evidence suggests that the latter may play a more prominent role in the elevation of pulmonary vascular resistance because the thickened smooth muscle cell layer caused by chronic hypoxia (CH) in small pulmonary arteries has been found to have no significant impact on luminal diameter. 5 Moreover, inhibition of Rho kinase, a mediator of myofilament contractility, has been shown to acutely reverse the increase in pulmonary arterial pressure in chronically hypoxic rats. 6 Based on these findings, it appears that contraction of smooth muscle during CH is the major factor contributing to the pathogenesis of hypoxic pulmonary hypertension.Although the cellular mechanisms underlying the development of pulmonary hypertension remain poorly understood, both growth and contraction of pulmonary arterial smooth muscle cells (PASMCs) are associated with alterations in

Mammalian homologs of transient receptor potential (TRP) genes in Drosophila encode TRPC proteins, which make up cation channels that play several putative roles, including Ca2+ entry triggered by depletion of Ca2+ stores in endoplasmic reticulum (ER). This capacitative calcium entry (CCE) is thought to replenish Ca2+ stores and contribute to signaling in many tissues, including smooth muscle cells from main pulmonary artery (PASMCs); however, the roles of CCE and TRPC proteins in PASMCs from distal pulmonary arteries, which are thought to be the major site of pulmonary vasoreactivity, remain uncertain. As an initial test of the possibility that TRPC channels contribute to CCE and Ca2+ signaling in distal PASMCs, we measured [Ca2+]i by fura-2 fluorescence in primary cultures of myocytes isolated from rat intrapulmonary arteries (>4th generation). In cells perfused with Ca2+-free media containing cyclopiazonic acid (10 microM) and nifedipine (5 microM) to deplete ER Ca2+ stores and block voltage-dependent Ca2+ channels, restoration of extracellular Ca2+ (2.5 mM) caused marked increases in [Ca2+]i whereas MnCl2 (200 microM) quenched fura-2 fluorescence, indicating CCE. SKF-96365, LaCl3, and NiCl2, blocked CCE at concentrations that did not alter Ca2+ responses to 60 mM KCl (IC50 6.3, 40.4, and 191 microM, respectively). RT-PCR and Western blotting performed on RNA and protein isolated from distal intrapulmonary arteries and PASMCs revealed mRNA and protein expression for TRPC1, -4, and -6, but not TRPC2, -3, -5, or -7. Our results suggest that CCE through TRPC-encoded Ca2+ channels could contribute to Ca2+ signaling in myocytes from distal intrapulmonary arteries.