Figure 1.

Proposed mechanisms by which the genes associated with pulmonary arterial hypertension (PAH; based on emerging genetic sequencing studies) and the Wnt signaling cascade (based on the current study by Hemnes and colleagues) functionally interact with the Ca²⁺ signaling pathway to cause pulmonary arterial smooth muscle cell (PASMC) contraction and pulmonary vasoconstriction, PASMC proliferation/migration and pulmonary vascular wall thickening, and inhibition of PASMC apoptosis resulting in pulmonary vascular remodeling (19). On the basis of case–control studies, the current work by Hemnes and colleagues has found Wnt pathway and smooth muscle contraction pathway variants to be significantly overrepresented in PAH and in vasodilator-responsive PAH, respectively (19). Activation of Wnt signaling has been shown to induce Ca²⁺ release from the sarcoplasmic (SR) or endoplasmic (ER) reticulum by inositol 1,4,5-trisphosphate (IP₃)-mediated activation of IP₃ receptor, a Ca²⁺ release channel expressed in the ER/SR membrane. The Wnt-mediated Ca²⁺ mobilization from the SR/ER to the cytosol causes Ca²⁺ store depletion that subsequently opens the store-operated Ca²⁺ channels (SOC), formed by Orai1/2 and TRPC6 channel subunits, to induce store-operated Ca²⁺ entry (SOCE). Mutations in genes encoding KCNK3, a two-pore domain K⁺ channel, and KCNA5, a voltage-gated K⁺ channel, may lead to transcriptional down-regulation and/or functional inhibition of KCNK3 and KCNA5, causing membrane depolarization that opens voltage-dependent Ca²⁺ channels (VDCC) and induces voltage-dependent Ca²⁺ entry. Furthermore, up-regulated Notch3 and enhanced Notch signaling have been demonstrated to functionally activate receptor-operated Ca²⁺ channels (ROC) and induce receptor-operated Ca²⁺ entry (ROCE) via Notch intracellular domain (NICD) or other unknown mechanisms (22). Caveolin-1 (CAV1) has been shown to inhibit various K⁺ channels, cause membrane depolarization, and induce Ca²⁺ influx through VDCC. The increased cytosolic Ca²⁺ concentration ([Ca²⁺]_cyt) causes PASMC contraction, leading to pulmonary vasoconstriction, and stimulates PASMC migration and proliferation, leading to pulmonary vascular remodeling (or concentric pulmonary arterial wall thickening). Bone morphogenetic protein (BMP)/bone morphogenetic protein receptor type 2 (BMPR2)/Smad signaling has been demonstrated to induce PASMC apoptosis and inhibit PASMC and pulmonary arterial endothelial cell (PAEC) proliferation (23, 24). Mutations in the BMPR2 gene identified in patients with idiopathic and heritable PAH result in the inhibition of PASMC apoptosis and enhancement of PASMC/PAEC proliferation, contributing to the development and progression of pulmonary vascular remodeling. Calmodulin (CaM) is a Ca²⁺-sensitive protein that physically interacts with Smad and induces Ca²⁺-dependent inhibition of transforming growth factor β/activin signaling (25, 26); this suggests that elevated [Ca²⁺]_cyt and activated CaM can lead to inhibition of BMP/BMPR2/Smad signaling, and ultimately to inhibited PASMC apoptosis and enhanced PASMC proliferation. DSH = dishevelled; ENG = endoglin; LRP = low-density lipoprotein receptor–related protein; Smad = mothers against decapentaplegic homologs.