HIF-1α and VEGF: Immunohistochemical Profile and Possible Function in Human Aortic Valve Stenosis

Abstract

Calcific aortic stenosis (CAS) is the most common valvular disease in Western countries. Histological findings in patients with CAS extremely resemble those of atherosclerosis and include accumulation and modification of lipoproteins, inflammation, extracellular matrix remodeling, and calcification. Angiogenesis is another prominent feature of CAS; however, there is only a limited amount of data available regarding the mechanisms behind the pathological neovascularization of a structure that is originally avascular. The present study aims to identify the molecular basis that regulates blood vessel growth in stenotic aortic valves, focusing on the role of HIF-1α and VEGF pathway. A total of 19 native degenerating aortic valves obtained at valve replacement surgery have been processed for Western blot, immunohistochemical, morphometric, and ultrastructural analyses. First, we have demonstrated the adverse ECM remodeling and the significant thickening of the leaflet also showing that HIF-1α and VEGF are significantly upregulated in the stenotic valves, are locally produced and colocalize with angiogenesis and areas of calcification. Next, we have characterized, for the first time to the best of our knowledge, the morphological features of the neovasculature evidencing the presence of intact blood vessels in close proximity to the mineralized zones. These results suggest that the complex structural remodeling of the matrix might reduce oxygen availability in the valve cusp contributing to the stabilization of HIF-1α that in turn induces a metabolic adaptation through the upregulation of VEGF and the formation of new blood vessels not only to overcome the hypoxic state but also to sustain the calcification process.

Differential cell-matrix responses in hypoxia-stimulated aortic versus mitral valves

“…HIF-1a, a marker frequently associated with angiogenesis, has recently been identified histologically in CAVD [21,22]. The impact of hypoxia on HIF-1a activation rsif.royalsocietypublishing.org J. R. Soc.…”

“…Studies have shown that hypoxia inducible factor 1-alpha (HIF-1a) is present in calcific nodules in CAVD [21,22]. Valve architecture, which greatly affects oxygen diffusion and transport, is different between the aortic and mitral valves.…”

Hypoxia, HIF, and Associated Signaling Networks in Chronic Kidney Disease

“…In addition, clinical data also implicate close relationship between HIF and vascular calcification. Both HIF-1α and HIF-2α activation have been localized in calcified aorta valve [129,130]. Li G et al also showed that elevated serum HIF-1α may be involved in coronary artery calcification by analysis of the computed tomography scanning data of 405 patients with type 2 diabetes mellitus [131].…”

Macrophages Promote Aortic Valve Cell Calcification Through STAT3 Splicing

“…Vegfa and Icam1 transcription: two signaling markers previously described in CAVD. 55,56 Importantly, STAT3β not only opposes STAT3α activity, thereby decreasing RUNX2 transcription, but also directly binds to RUNX2, preventing its activity as a transcription factor. 57 These phenomena translated to human AVs: STAT3β decreases in calcified regions of diseased AVs and negatively correlates with RUNX2 expression.…”