Mechanism of Hypoxia-Mediated Smooth Muscle Cell Proliferation Leading to Vascular Remodeling

Figure 3

Hypoxia can lead to the effect of AMPK pathway, and the increased expression of HIF-1 promotes the effect on SMCs. (1) Hypoxia inhibits mitochondrial production of α-OG by promoting the AMPK pathway, which inhibits the expression of PHDs and promotes the expression of HIF-1α. (2) Hypoxia inhibits the expression of PHDs, resulting in stable expression of HIF-1α and increased expression of PDK1, which promotes the expression of ROS, which in turn inhibits the hydroxylation of HIF-1α by PHDs. (3) HIF-1α and HIF-1β translocate to the nucleus to bind to hypoxic elements and regulate the transcription and translation of genes related to cell proliferation [104]. (4) HIF-1 promotes PDGF expression and PDGF binds to corresponding receptors to activate SOCC, MAPK, PI3K/Akt, and JAK/STAT3 signaling pathways [105]. (5) PDGF induces transactivation of cyclin D1 and survival proteins in SMC through phosphorylation of STAT3, thereby promoting SMC proliferation and migration and reducing apoptotic cell death [106]. (6) PDGF induces the breakdown of phosphatidylinositol 4,5-bisphosphate (PLCγ) to IP3 and diacylglycerol (DAG), which binds to receptors on the ER and stimulates the release of [Ca²⁺] from the calcium pool to the cytoplasm [103]. DAG stimulates VSMC proliferation via the PKC/Ras/MAPK pathway.