Angiogenic modulators in valve development and disease: does valvular disease recapitulate developmental signaling pathways?

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Abstract
Neovascularization is a recognized feature of many valvular diseases and is established by numerous angiogenic modulators. Less known is that angiogenic modulators are multifunctional and have additional roles in valve development and disease. Recent advancements in this area are described. Initiation of epithelial to mesenchymal transformation, a developmental induction that specifies primordial interstitial cells (mesenchymal cells), requires vascular endothelial growth factor A, which stimulates matrix metalloproteinase 2 production and the invasive migration of mesenchymal cells. Epithelial to mesenchymal transformation also requires the matrix component hyaluronan to facilitate signaling through ErbB2/ErbB3 receptors and then is terminated by an increase in vascular endothelial growth factor A expression. Fibroblast growth factor 4 has been implicated in stimulating the following stage of proliferative expansion. Subsequently, in the remodeling phase, heparin-binding epidermal growth factor-like growth factor limits mesenchymal cell proliferation by signaling through the EGFR/ErbB1 receptor. Many adult valvular lesions appear similar to the embryonic proliferative expansion phase as they exhibit accumulations of extracellular matrix and myofibroblasts (a mesenchyme-like interstitial cell). The origins of such lesions may involve transforming growth factor beta 1. Similar to epithelial to mesenchymal transformation, tumor growth factor beta1 can induce cultured valvular endothelial cells to transdifferentiate to a myofibroblast-like phenotype. This scenario may occur in carcinoid valve disease because serotonin can induce interstitial cell expression of tumor growth factor beta1. Additionally, prolonged tumor growth factor beta1 activity may predispose to calcific degeneration. Calcific leaflets also exhibit tenascin-C, which may facilitate inflammatory cell migration through upregulation of pro-matrix metalloproteinase 2. Numerous angiogenic modulators control multiple stages of valvulogenesis and in the context of adult valvular disease may recapitulate their embryonic roles. Thus, lessons learned from valvulogenesis may provide insights into the molecular basis of adult valvular disease.