Abstract
Blood vessels and lymphatic vessels are located in many tissues and organs throughout the body, and play important roles in a wide variety of prevalent diseases in humans. Vascular endothelial growth factor-D (VEGF-D) is a secreted protein that can promote the remodeling of blood vessels and lymphatics in development and disease. Recent fundamental and translational studies have provided insight into the molecular mechanisms by which VEGF-D exerts its effects in human disease. Hence this protein is now of interest as a therapeutic and/or diagnostic target, or as a potential therapeutic agent, in a diversity of indications in cardiovascular medicine, cancer and the devastating pulmonary condition lymphangioleiomyomatosis. This has led to clinical trial programs to assess the effect of targeting VEGF-D signaling pathways, or delivering VEGF-D, in angina, cancer and ocular indications. This review summarizes our understanding of VEGF-D signaling in human disease, which is largely based on animal disease models and clinicopathological studies, and provides information about the outcomes of recent clinical trials testing agonists or antagonists of VEGF-D signaling.
Highlights
Vascular endothelial growth factor-D (VEGF-D) is a secreted glycoprotein that can activateVEGF receptors on the endothelium, is a mitogen for endothelial cells and promotes the growth and remodeling of blood vessels and lymphatic vessels [1,2].These vessels are located in many parts of the body and participate in a wide variety of prevalent human diseases
Given that VEGF-C and VEGF-D can activate signaling for proliferation of vascular endothelial cells and angiogenesis [2,64], and have been reported to promote edema in certain animal models [54,65], there has been interest in targeting these growth factors in Wet age-related macular degeneration (wet AMD) as a strategy to further enhance the restriction of pathological neovascularization and vascular leakage achieved with currently used drugs
Studies in a diabetic mouse model showed that blockade of VEGF-C and VEGF-D with a soluble form of VEGF receptor (VEGFR)-3 can modulate adipose tissue inflammation, which was associated with reduced hepatic lipid accumulation and improved insulin sensitivity indicating an unanticipated function of lymphangiogenic factors in mediating metabolic syndrome-associated adipose tissue inflammation [105]
Summary
Vascular endothelial growth factor-D (VEGF-D) is a secreted glycoprotein that can activate. VEGF receptors on the endothelium, is a mitogen for endothelial cells and promotes the growth and remodeling of blood vessels and lymphatic vessels [1,2] (see Section 3 for further information). These vessels are located in many parts of the body and participate in a wide variety of prevalent human diseases. VEGF-D signaling are listed to the right with “PlGF” denotesthat placenta factor, Ig denotes immunoglobulin, CUB denotes complement-binding, denotesNote a domain found inVEGFR-3 post synaptic protein “Mab” denoting monoclonal PDZ antibody. CUB denotes complement-binding, PDZ denotes a domain found in post synaptic density protein
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