Differential expression of vascular endothelial growth factor isoforms and receptor subtypes in the infarcted heart
ABSTRACT AIMS: The vascular endothelial growth factor (VEGF) family contains four major isoforms and three receptor subtypes. The expressions of each VEGF isoform and receptor subtype in cardiac repair/remodeling after myocardial infarction (MI) remain uncertain and are investigated in the current study. METHODS AND RESULTS: Temporal and spatial expressions of VEGF isoforms and VEGFR subtypes were examined in the infarcted rat heart. Sham-operated rats served as controls. We found that the normal myocardium expressed all VEGF isoforms. Following MI, VEGF-A was only increased in the border zone at day 1 and was significantly decreased in the infarcted heart during the 42day observation period afterwards. VEGF-B was significantly suppressed in the infarcted heart. VEGF-C and VEGF-D were markedly increased in the infarcted heart in both early and late stages of MI. VEGFR-1 and 2 were significantly decreased in the infarcted heart, while VEGFR-3 was significantly increased, which was primarily expressed in blood vessels and myofibroblasts (myoFb). CONCLUSIONS: VEGF isoforms and VEGFR subtypes are differentially expressed in the infarcted heart. Increased VEGF-A in the very early stage of MI suggests the potential role in initiating the cardiac angiogenic response. Suppressed cardiac VEGF-B postMI suggests that it may not be critical to cardiac repair. The presence of enhanced VEGF-C and VEGF-D along with its receptor, VEGFR-3, in various cell types of the infarcted heart suggest that these isoforms may regulate multiple responses during cardiac repair/remodeling.
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ABSTRACT: Vascular endothelial growth factor-B (VEGF-B), discovered over 15 years ago, has long been seen as one of the more ambiguous members of the VEGF family. VEGF-B is produced as two isoforms: one that binds strongly to heparan sulfate in the pericellular matrix and a soluble form that can acquire binding via proteolytic processing. Both forms of VEGF-B bind to VEGF-receptor 1 (VEGFR-1) and the neuropilin-1 (NRP-1) coreceptor, which are expressed mainly in blood vascular endothelial cells. VEGF-B-deficient mice and rats are viable without any overt phenotype, and the ability of VEGF-B to induce angiogenesis in most tissues is weak. This has been a puzzle, as the related placenta growth factor (PlGF) binds to the same receptors and induces angiogenesis and arteriogenesis in a variety of tissues. However, it seems that VEGF-B is a vascular growth factor that is more tissue specific and can have trophic and metabolic effects, and its binding to VEGFR-1 shows subtle but important differences compared with that of PlGF. VEGF-B has the potential to induce coronary vessel growth and cardiac hypertrophy, which can protect the heart from ischemic damage as well as heart failure. In addition, VEGF-B is abundantly expressed in tissues with highly active energy metabolism, where it could support significant metabolic functions. VEGF-B also has a role in neuroprotection, but unlike other members of the VEGF family, it does not have a clear role in tumor progression. Here we review what is hitherto known about the functions of this growth factor in physiology and disease.Physiological Reviews 07/2014; 94(3):779-794. DOI:10.1152/physrev.00028.2013 · 29.04 Impact Factor
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ABSTRACT: Aim: Vascular endothelial growth factor (VEGF)-C is a key mediator of lymphangiogenesis. Our recent study shows that VEGF-C/VEGF receptors (VEGFR)-3 are significantly increased in the infarcted rat myocardium, where VEGFR-3 is expressed not only in lymph ducts, but also in myofibroblasts, indicating that VEGF-C has an unrevealed role in fibrogenesis during cardiac repair. The current study is to explore the regulation and molecular mechanisms of VEGF-C in fibrogenesis. Methods and Results: The potential regulation of VEGF-C on myofibroblast differentiation/growth/migration, collagen degradation/synthesis and transforming growth factor (TGF)-β and ERK pathways was detected in cultured cardiac myofibroblasts. Our results showed that VEGF-C significantly increased myofibroblast proliferation, migration and type I/III collagen production. Matrix metalloproteinase (MMP)-2 and -9 were significantly elevated in the medium of VEGF-C treated cells, coincident with increased tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-2. Furthermore, VEGF-C activated TGF-β1 pathway and ERK phosphorylation, which was significantly suppressed by TGF-β or ERK blockade. Conclusions: This is the first study indicating that in addition to lymphangiogenesis, VEGF-C is also involved in fibrogenesis through stimulation of myofibroblast proliferation, migration and collagen synthesis, via activation of the TGF-β1 and ERK pathways.AJP Heart and Circulatory Physiology 01/2014; 306(6). DOI:10.1152/ajpheart.00559.2013 · 4.01 Impact Factor