Open AccessHydrogen sulfide improves postischemic neoangiogenesis in the hind limb of cystathionine‐ β ‐synthase mutant mice via PPAR ‐ γ / VEGF axis
Author(s) -
Majumder Avisek,
Singh Mahavir,
George Akash K.,
Behera Jyotirmaya,
Tyagi Neetu,
Tyagi Suresh C.
Publication year - 2018
Publication title -
physiological reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.918
H-Index - 39
ISSN - 2051-817X
DOI - 10.14814/phy2.13858
Subject(s) - cystathionine beta synthase , hindlimb , vascular endothelial growth factor , medicine , endocrinology , peroxisome proliferator activated receptor , enos , arteriogenesis , nitric oxide synthase , chemistry , biology , biochemistry , ischemia , receptor , nitric oxide , methionine , vegf receptors , amino acid
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 ( HH cy), 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 HH cy‐mediated neoangiogenic defects. Hydrogen sulfide (H 2 S) 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 H 2 S. We hypothesized that exogenous supplementation of H 2 S might improve HH cy‐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 GYY 4137 (a long‐acting H 2 S 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 mRNA s levels were studied by Western blots and qPCR analyses. HIF 1‐ α , VEGF , PPAR ‐ γ and p‐ eNOS expressions were attenuated in skeletal muscle of CBS +/− mice after 21 days of FAL in comparison to wild‐type ( WT ) mice, that were improved via GYY 4137 treatment. We also found that the collateral vessel density and blood flow were significantly reduced in post‐ FAL CBS +/− mice compared to WT mice and these effects were ameliorated by GYY 4137. Moreover, we found that plasma nitrite levels were decreased in post‐ FAL CBS +/− mice compared to WT mice, which were mitigated by GYY 4137 supplementation. These results suggest that HH cy can inhibit neoangiogenesis via antagonizing the angiogenic signal pathways encompassing PPAR ‐ γ / VEGF axis and that GYY 4137 could serve as a potential therapeutic to alleviate the harmful metabolic effects of HH cy conditions.