Characterization of the sex-specific pattern of angiogenesis and lymphangiogenesis in aortic stenosis

Abstract

ObjectiveWe aim to analyze sex-related differences in angiogenesis and lymphangiogenesis in aortic valves (AVs) and valve interstitial cells (VICs) from aortic stenosis (AS) patients.Approach and ResultsTotally 230 patients (59% men) with severe AS undergoing surgical valve replacement were recruited. The density of total neovessels was higher in AVs from men as compared to women. Both small and medium neovessels were more abundant in men's AVs. Accordingly, male AVs exhibited higher CD31 and VE-cadherin expressions. The levels of the pro-angiogenic markers, such as vascular endothelial growth factor (VEGF)-A, VEGF receptor (VEGFR)1, VEGFR2, insulin-like growth factor-binding protein-2 (IGFBP-2), interleukin (IL)-8, chemerin, and fibroblast growth factor (FGF)-7, were increased in AVs from men. Transforming growth factor-β expression was higher in male AVs. The expression of antiangiogenic molecules thrombospondin (Tsp)-1, endostatin, and CD36 was upregulated in male AVs, although the levels of Tsp-2, IL-4, IL-12p70, and chondromodulin-1 were similar between both sexes. The number of lymphatic vessels and the expression of the lymphangiogenic markers Lyve-1 and D2-40 was higher in men's AV as well as VEGF-C, VEGF-D, and VEGFR3. Multivariate analyses adjusted for confounders further validated the sex-dependent expression of these targets. VICs isolated from men's AVs secreted higher amounts of the pro-angiogenic factors, VEGF-A, VEGFR1, IGFBP-2, and FGF-7, as well as the pro-lymphangiogenic factors, VEGF-C, VEGF-D, and VEGFR3, than women without changes in antiangiogenic markers.ConclusionOur data show that aberrant angiogenic and lymphangiogenic cues are over-represented in male AVs. Importantly, the VIC is a relevant source of multiple morphogens involved in angiogenesis and lymphangiogenesis likely endowing the AV of men with the predominant calcific AS phenotypes.

Unraveling the Role of Sex in Endothelial Cell Dysfunction: Evidence From Lineage Tracing Mice and Cultured Cells

“…46 Also, recent studies provided evidence that male rats and humans are more prone to corneal neovascularization than females and that males had a higher level of pro-atherogenic molecules, including VEGF (vascular endothelial growth factor)-A, VEGF receptor (VEGFR)1, VEGFR2, and IGFBP2, than females. 47,48 In contrast, Rudnicki et al 49 showed that female adipose mice and human EC have higher proliferation and angiogenesis and less inflammation than male adipose EC females. In addition, using male and female human umbilical vein EC, Cattaneo et al 50 observed that male cells had higher apoptotic rates in response to serum starvation conditions and identified protein PTX3 (pentraxin-related protein 3) as a potential mediator of this apoptotic response and discovered that female EC expressed higher levels of eNOS (endothelial nitric oxide synthase).…”

Sex‐dependent expression of galectin‐1, a cardioprotective β‐galactoside‐binding lectin, in human calcific aortic stenosis

“…Gal‐1 is considerably up‐regulated in inflammatory and hypoxic environments, 37,45 partly mediated by HIF‐1α‐independent, NF‐kB‐dependent pathways 46 . Calcification of the AV triggers hypoxia and aberrant pro‐osteogenic angiogenesis 30,47,48 . Gal‐1 was positively associated with markers of inflammation, oxidative stress, ECM, angiogenesis, and osteogenesis within the stenotic AV.…”

“…46 Calcification of the AV triggers hypoxia and aberrant pro-osteogenic angiogenesis. 30,47,48 Gal-1 was positively associated with markers of inflammation, oxidative stress, ECM, angiogenesis, and osteogenesis within the stenotic AV. Together with the macrophage infiltrates, active and osteochondrogenic VICs were a source of Gal-1 in AS.…”

“…Moreover, our results reveal that rather than the inflammatory infiltrates, the active VIC is a relevant source of Gal-1. Indeed, calcifying men's VICs highly secreted Gal-1 to the extracellular site in association with pathogenic markers 7,30 and glucose metabolism. Importantly, βestradiol regulated the expression of Gal-1, likely by binding the LGALS1 promoter.…”

The MRI features of renal inflammatory pseudotumor: A case report and literature review

“…[ 2 ] Inflammation lasting for a long time can induce angiogenesis which is vulnerable and easy to bleed. [ 26 ] Under the microscope, the histologic examination of most cases reveals the bulk of the mass to contain spindle cells admixed with collagen, lymphocytes and plasma cells which it is also known as inflammatory myofibroblastic tumor. [ 25 ] The spindle cells which have myofibroblastic features and are of fibroblastic or myofibroblastic origin express Vimentin and SMA.…”