Fig. 8

Hypothetical mechanism underlying the protection of vascular and barrier functions by the combination of acetazolamide and RIPC during hypoxic exposure. During hypoxia, PDGF-A interacts with PDGFRα distributed on perivascular regions. The activation of PDGFA/PDGFRα pathway results in an increase in MMP and ADAM expression. These enzymes break down the extracellular matrix collagen and degrade the tight junction proteins, leading to barrier dysfunction, leakage, edema, and ultimately, acute mountain sickness. PDGF-B also participates in PDGFRα pathway and interacts with PDGFRβ located on pericytes. Under hypoxic conditions, the activation of PDGF-B/PDGFRβ pathway leads to abnormal angiogenesis and aberrant vessel morphology. The permeability of the immature neogenetic vessel increases, which contributes to leakage and acute mountain sickness. Our findings revealed that before hypoxic exposure, acetazolamide, and RIPC synergistically reduce PDGF-AB levels, which probably “precondition” blood vessels prior to hypoxia, consequently minimizing the hypoxic damages