Reverse Regulatory Pathway (H(2)S / PGE(2) / MMP) in Human Aortic Aneurysm and Saphenous Vein Varicosity

Hydrogen sulfide (H(2)S) is a mediator with demonstrated protective effects for the cardiovascular system. On the other hand, prostaglandin (PG)E(2) is involved in vascular wall remodeling by regulating matrix metalloproteinase (MMP) activities. We tested the hypothesis that endogenous H(2)S may modulate PGE(2), MMP-1 activity and endogenous tissue inhibitors of MMPs (TIMP-1/-2). This regulatory pathway could be involved in thinning of abdominal aortic aneurysm (AAA) and thickening of saphenous vein (SV) varicosities. The expression of the enzyme responsible for H(2)S synthesis, cystathionine-γ-lyase (CSE) and its activity, were significantly higher in varicose vein as compared to SV. On the contrary, the endogenous H(2)S level and CSE expression were lower in AAA as compared to healthy aorta (HA). Endogenous H(2)S was responsible for inhibition of PGE(2) synthesis mostly in varicose veins and HA. A similar effect was observed with exogenous H(2)S and consequently decreasing active MMP-1/TIMP ratios in SV and varicose veins. In contrast, in AAA, higher levels of PGE(2) and active MMP-1/TIMP ratios were found versus HA. These findings suggest that differences in H(2)S content in AAA and varicose veins modulate endogenous PGE(2) production and consequently the MMP/TIMP ratio. This mechanism may be crucial in vascular wall remodeling observed in different vascular pathologies (aneurysm, varicosities, atherosclerosis and pulmonary hypertension).