FIGURE 1.

Proposed role of alteration in IP₃R expression/function in the development of hypertension. Apart from contribution to vascular tone and VSM contractility via SR-Ca²⁺ release, calcium wave production, and induction of calcium sensitization, IP3R forms a mechanosensing complex with TRP channels that is proposed to initiate contraction in response to increased intraluminal pressure. Physiological patterns of IP₃R-mediated Ca²⁺ release are affected by the expression of other SR membrane proteins including SERCA. Under circumstances of sustained increased blood pressure, IP₃R expression increases together with increased sensitivity to IP₃ and increased coupling with the TRP mechanosensing machinery resulting in increased intracellular Ca²⁺ release and increased VSM contraction. Interplay with NFAT-mediated signaling pathways might contribute pressure-induced changes in VSMC phenotype, vascular inflammation, and VSMC senescence. Increased VSMC proliferation and migration were reported to involve increased IP₃R-mediated Ca²⁺ release with subsequent intracellular store depletion and increased store-operated Ca²⁺ entry. IP₃R-mediated Ca²⁺ release can potentially relay apoptotic signaling to the mitochondria contributing to vascular aging.