Hydrogen sulfide improves postischemic neoangiogenesis in the hind limb of cystathionine‐β‐synthase mutant mice via PPAR‐γ/VEGF axis

摘要

Neoangiogenesis is a fundamental process which helps to meet energy requirements, tissue growth, and wound healing. Although previous studies showed that Peroxisome proliferator‐activated receptor (PPAR‐γ) regulates neoangiogenesis via upregulation of vascular endothelial growth factor (VEGF), and both VEGF and PPAR‐γ expressions were inhibited during hyperhomocysteinemic (HHcy), whether these two processes could trigger pathological effects in skeletal muscle via compromising neoangiogenesis has not been studied yet. Unfortunately, there are no treatment options available to date for ameliorating HHcy‐mediated neoangiogenic defects. Hydrogen sulfide (H2S) is a novel gasotransmitter that can induce PPAR‐γ levels. However, patients with cystathionine‐β‐synthase (CBS) mutation(s) cannot produce a sufficient amount of H2S. We hypothesized that exogenous supplementation of H2S might improve HHcy‐mediated poor neoangiogenesis via the PPAR‐γ/VEGF axis. To examine this, we created a hind limb femoral artery ligation (FAL) in CBS ^+/− mouse model and treated them with GYY4137 (a long‐acting H2S donor compound) for 21 days. To evaluate neoangiogenesis, we used barium sulfate angiography and laser Doppler blood flow measurements in the ischemic hind limbs of experimental mice post‐FAL to assess blood flow. Proteins and mRNAs levels were studied by Western blots and style="fixed-case">qPCR analyses. style="fixed-case">HIF1‐α, style="fixed-case"> VEGF, style="fixed-case"> PPAR‐γ and p‐ style="fixed-case">eNOS expressions were attenuated in skeletal muscle of style="fixed-case">CBS ^+/− mice after 21 days of style="fixed-case">FAL in comparison to wild‐type ( style="fixed-case">WT) mice, that were improved via style="fixed-case">GYY4137 treatment. We also found that the collateral vessel density and blood flow were significantly reduced in post‐ style="fixed-case">FAL CBS ^+/− mice compared to style="fixed-case">WT mice and these effects were ameliorated by style="fixed-case">GYY4137. Moreover, we found that plasma nitrite levels were decreased in post‐ style="fixed-case">FAL CBS ^+/− mice compared to style="fixed-case">WT mice, which were mitigated by style="fixed-case">GYY4137 supplementation. These results suggest that style="fixed-case">HHcy can inhibit neoangiogenesis via antagonizing the angiogenic signal pathways encompassing style="fixed-case">PPAR‐γ/ style="fixed-case">VEGF axis and that style="fixed-case">GYY4137 could serve as a potential therapeutic to alleviate the harmful metabolic effects of style="fixed-case">HHcy conditions.