Cystathionine γ-lyase is expressed in human atherosclerotic plaque microvessels and is involved in micro-angiogenesis.

Atherosclerotic plaques are classically divided into stable and vulnerable plaques. Vulnerable plaques are prone to rupture with a risk for infarction. High intraplaque microvessel density predisposes to plaque vulnerability. Hydrogen sulfide (H2S) is a proangiogenic gasotransmitter which is endogenously produced by cystathionine γ-lyase (CSE), and is believed to have vasculoprotective effects. However, due to its proangiogenic effects, H2S may result in pathological angiogenesis in atherosclerotic plaques, thereby increasing plaque vulnerability. The aim of this study was to determine CSE expression pattern in atherosclerotic plaques, and investigate whether CSE is involved in micro-angiogenesis in vitro. Endarterectomy plaques were studied for CSE expression, and the role of CSE in micro-angiogenesis was studied in vitro. CSE is expressed in plaques with similar levels in both stable and vulnerable plaques. CSE co-localized with von Willebrand Factor-positive microvessel endothelial cells and alpha-smooth-muscle actin-positive SMCs. In vitro, inhibition of CSE in HMEC-1 reduced tube formation, cell viability/proliferation, and migration which was restored after culture in the presence of H2S donor GYY4137. CSE is expressed in intraplaque microvessels, and H2S is a stimulator of micro-angiogenesis in vitro. Due to this pro-angiogenic effect, high levels of CSE in atherosclerotic plaques may be a potential risk for plaque vulnerability.

CD16⁺ monocytes with smooth muscle cell characteristics are reduced in human renal chronic transplant dysfunction.

In chronic transplant dysfunction (CTD), persistent (allo)immune-mediated inflammation eventually leads to tissue remodeling including neointima formation in intragraft arteries. We previously showed that recipient-derived neointimal α-SMA(+) smooth muscle-like cells are present in human renal allografts with CTD. Human PBMC contain myeloid cells capable of differentiating into α-SMA(+) cells in vitro; the phenotype of the ancestral subset is as yet unknown. This study aimed to investigate whether monocyte subsets contain cells with smooth muscle-like cell differentiation capacity and whether CTD in renal transplant recipients is associated with a shift in these monocyte subsets. To accomplish this goal, monocyte subsets from healthy controls were sorted based on CD14 and CD16 expression to investigate gene expression levels of mesenchymal markers α-SMA and SM22α. CD14(+)/CD16(++) monocytes displayed increased α-SMA and SM22α mRNA expression compared with CD14(++)/CD16(-) monocytes, suggesting increased differentiation potential toward smooth muscle-like cells. Flow cytometry revealed that in non-CTD transplant recipients the percentage of CD14(+)/CD16(++) monocytes was reduced, with an even further reduction in patients with CTD. To determine a potential correlation between CD14(+)/CD16(++) monocytes and α-SMA(+) cell outgrowth potential in vitro, PBMC of healthy controls and transplant recipients with and without CTD were cultured under fibrotic culture conditions, and indeed a significant correlation (p=0.0002, r=0.62) was observed. Finally, double staining for α-SMA and CD16 revealed presence of α-SMA(+)CD16(+) cells in kidney explants from CTD patients, albeit at very low numbers. Our data represent evidence that, compared to CD14(++)CD16(-) monocytes, CD14(+)CD16(++) monocytes have an increased expression of smooth muscle cell-associated genes. This monocyte subpopulation is reduced in renal transplant patients with CTD, possibly due to selective migration into the allograft.