Figure 4.

Adrenergic receptor signaling, intracellular calcium, and pulmonary artery smooth muscle cell proliferation. In pulmonary artery smooth muscle cells (PASMC), β-adrenergic receptor (AR) activates adenylyl cyclase (AC) to increase cAMP and, thereby, activate protein kinase A (PKA). PKA phosphorylates phospholamban (PLN) and increase activity of the sarcoplasmic reticulum Ca²⁺-ATPase (SERCA2), which decreases intracellular Ca²⁺ levels. In pulmonary hypertension, SERCA2 expression is downregulated. This results in high intracellular Ca²⁺ levels through the actions of the ryanodine receptors (RYR) and α-AR signaling. The elevated levels of intracellular Ca²⁺ stimulate proliferation through protein phosphatase 2B (PP2B), translocation of nuclear factor of activated T cells (NFAT) to the nucleus to promote transcription of cyclin D1. PLC, phospholipase C, inositol triphosphate.