Biology subjects

Allagnat, F.

Publications and source records attributed to Allagnat, F..

3 recordsLinked to original sources

bioRxiv2024

Impaired glycolysis in aged endothelial cells is associated with reduced neovascularisation upon tissue ischemia

The vascular system experiences an age-associated decline in tissue perfusion and response to ischemic diseases. The factors driving this age-associated neovascularization decline remain unclear. While old endothelial cells (ECs) adopt a pro-angiogenic gene expression profile, we observed a stark reduction in the proliferative capacity of old ECs, while migratory capabilities remain intact. This is paralleled by a drastic decline in glycolytic capacity and ATP production, which likely act as limiting factors to neovascularization. These findings may provide new strategies to restore EC function in aging, thereby improving organ resilience and extending health- and lifespan.

molecular biology↗

bioRxiv2023

The hydrogen sulfide donor sodium thiosulfate limits inflammation but aggravate smooth muscle cells apoptosis and aneurysm progression in a mouse model of abdominal aortic aneurysm

IntroThe prevalence of abdominal aortic aneurysm (AAA) is constantly progressing with the aging of the global population. AAA rupture has a devastating 80% mortality rate and there is no treatment to slow-down AAA progression. Hydrogen sulfide (H2S) is a ubiquitous redox-modifying gasotransmitter produced in the cardiovascular system via the reverse trans-sulfuration pathway by cystathionine {gamma}-lyase (CSE). H2S has protective properties on the cardiovascular system, including anti-inflammatory and antioxidant effects. Here, we hypothesized that sodium thiosulfate (STS), a clinically relevant source of H2S, would limit AAA growth. Methods8-12 weeks old male WT or Cse-/- mice on a C57BL/6J genetic background were submitted to a model of AAA by topical elastase application on the abdominal aorta and {beta}-aminopropionitrile fumarate treatment in the drinking water for 2 weeks post-op. Sodium thiosulfate (STS) was given via the drinking water post-op until aorta collection. In vitro experiments were conducted to assess the effect of STS and pro-inflammatory cytokines interleukin-1 {beta} and 6 and tumor necrosis factor on primary human vascular smooth muscle cell (VSMC). ResultsSurprisingly, STS increased elastin degradation, AAA size and rupture, despite reducing infiltration of macrophages, antigen-presenting cells and lymphocytes in WT mice. Conversely, Cse-/- mice with impaired H2S production developed smaller AAA than WT mice despite increased infiltration of immune cells. STS reduced VSMC coverage, possibly lowered VSMC proliferation, and promoted VSMC loss and extracellular matrix (ECM) breakdown. In vitro, STS aggravated pro-inflammatory cytokine-induced VSMCs apoptosis. ConclusionSTS has a paradoxical effect on AAA growth, reducing inflammation while simultaneously impeding favorable vascular remodeling, resulting in bigger AAA in a model of periadventitial elastase. This study identifies a negative effect of H2S on VSMC in this environment, highlighting the complex role of H2S in AAA progression. The deleterious effect of STS on AAA progression is significant, especially given the growing use of STS in clinical settings for various indications.

physiology↗

bioRxiv2022

Cystathionine gamma lyase overexpression enhances neovascularization through NAD-dependent mechanisms

ObjectiveHydrogen sulfide (H2S) is a proangiogenic gas produced primarily by the transsulfuration enzyme cystathionine-gamma-lyase (CGL). CGL-dependant H2S production is required for neovasculariation in models of peripheral arterial disease. However, the benefits of increasing endogenous CGL and its mechanism of action have yet to be elucidated. Methods10 weeks old male whole-body CGL overexpressing mice (CGLTg) and wild type littermates (C57BL/6J) were subjected to the hindlimb ischemia model. Functional recovery was assessed through treadmill exercise endurance testing, while ischemic leg perfusion recovery was measured by laser Doppler perfusion imaging and tissue immunohistochemistry. To examine angiogenic potential, aortic ring sprouting assay and post-natal mouse retinal vasculature development studies were performed. Lastly, comparative metabolomics, NAD+/NADH analysis, and quantitative real-time PCR were performed on WT and CGLTg gastrocnemius muscles. ResultsThe restoration of blood flow upon femoral ligation occurred more rapidly in CGLTg mice. CGLTg mice were able to run further and for longer compared to WT mice. In ischemic gastrocnemius, capillary density was increased in mice overexpressing CGL. Endothelial cell sprouting was increased in aorta isolated from CGLTg mice, especially when cultured in VEGF-only media. Metabolomics analysis demonstrated an increased presence of niacinamide, a precursor of nicotinamide adenine dinucleotide (NAD+/ NADH) in the muscle of CGLTg mice. Finally, CGL overexpression and NMN supplementation improved endothelial cell migration in vitro. ConclusionsTaken together, our results demonstrate that CGL overexpression improves the neovascularization of skeletal muscle upon hindlimb ischemia. These effects are mediated by changes in the NAD pathway, which improves endothelial cell migration.

physiology↗