Reversal of Chronic Hypoxiainduced Alteration of Ca2 Signaling

A distinguishing characteristic of chronic hypoxia-induced PAHT is its reversibility upon return to normoxia. In addition to pulmonary vasoconstriction (Fig. 2A), right ventricular hypertrophy, structural changes in elastic laminea, muscularization of distal pulmonary vessels, upregulation of angiotensin II receptors, and inhibition of K+channels are also fully reversed after 2-3 weeks of normoxia recovery (9, 10, 12). Furthermore, the sustained increase in resting [Ca2+]j in PASMCs during chronic hypoxia is also reversed following normoxic recovery (Fig. 2B) (10). However, no detailed study has been performed on the reversibility of chronic hypoxia-induced alterations of agonist-induced [Ca2+)j oscillation in PASMCs. Our preliminary studies show that, after 3 weeks of normoxic recovery, both the oscillating profile of ET-1 -induced [Ca2+]j response and percentage of cells exhibiting Ca2+ oscillations are restored (Fig. 5).

Figure 5. Proposed cellular mechanisms responsible for agonist-induced Ca2+ oscillations in PASMCs and their alteration by chronic hypoxia. Agonists bind to specific G-protein coupled receptors and activate phospholipase C (PLC) which hydrolyses phosphatidylinositol 4, 5 biphosphate (PIP2) to diacyglycerol (DAG) and IP3. IP} then binds to specific IP3R on the SR membrane. The cyclical opening of the IP3R-Ca2+ releasè channels due to its biphasic regulation by cytosolic Ca2+ induces [Ca2+]i oscillations. Released Ca2+ is then sequestered into the SR by SERCA and/or extruded through the plasmalemmal Ca2+ pump (PMCA), thereby leading to a progressive diminution offCa2*^ oscillations. Activation of RyR on the SR membrane by caffeine also induces a transient rise in [Ca2+]j and contributes the overall Ca2+ signaling. Chronic hypoxia specifically alters [Ca2*], oscillations by regulating the IP3 signaling pathway (e.g., IP3production and/or IP3R function and expression) and/or SERCA.

Agonist

Agonist

Chronic Hypoxia

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