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: The aim was to test the hypothesis that cardiac angiotensin converting enzyme (ACE) is related to the accumulation of fibrous tissue in the heart. A model of tissue repair (pericardiotomy with left coronary artery ligation) was used, together with the following: quantitative in vitro autoradiography (125I-351A) to determine ACE binding density; immunohistochemistry (monoclonal ACE antibody, 9B9) to identify cells expressing ACE; and in situ hybridisation to localise cells expressing type I collagen mRNA. Age and sex matched rats receiving this operative procedure without subsequent infarction (sham operated) served as controls to those with left ventricular myocardial infarction. Serial heart sections obtained from each group at 3 days and at 1, 2, 4, and 8 weeks following operation were examined for morphological evidence of injury and inflammatory cells (haematoxylin/eosin) and fibrillar collagen (picrosirius red). Following myocardial infarction: (a) on day 3, neutrophils and macrophages were present at the site of infarction, while fibrillar collagen and ACE binding were not increased compared with control; (b) at week 1, fibrillar collagen and ACE binding were present at the site of infarction and became progressively more advanced at 2, 4, and 8 weeks; (c) at week 2, there was increased ACE binding in the right ventricle and interventricular septum, when perivascular fibrosis of intramural coronary arteries and microscopic scars appeared, together with endomyocardial fibrosis of the septum; (d) there was marked ACE binding in the fibrosed visceral pericardium two weeks after operation in both myocardial infarction and sham operated groups; (e) there was type I collagen mRNA expression on postoperative week 1, localised within fibroblasts or fibroblast-like cells found at infarct and fibrous tissue sites in the right ventricle, septum, and pericardium; and (f) ACE-labelled cells included fibroblast-like cells, as well as macrophages and endothelial cells. Thus in this model of tissue repair, marked ACE binding density is associated with fibrillar collagen formation that appears within and remote to the site of myocardial infarction, including the pericardium. Cardiac ACE, originating from type I collagen producing cells, therefore represents an integral component of fibrous tissue formation in this rat model of tissue injury.Cardiovascular Research 10/1994; 28(9):1423-32. · 5.94 Impact Factor
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ABSTRACT: Following left coronary artery ligation in the rat, markedly increased angiotensin converting enzyme (ACE) binding appears at the site of myocardial infarction (MI). This is also the case in fibrosed visceral pericardium that follows pericardiotomy alone (without MI). Immunohistochemical ACE labeling, using a monoclonal antibody, indicates fibroblast-like calls express ACE at each of these sites of tissue repair. It is unknown, however, whether these cells are phenotypically transformed fibroblasts containingα-smooth muscle actin (i.e. myofibroblasts). This study was therefore undertaken to determine whether myofibroblasts appear at the site of MI and pericardial fibrosis and their relationship to ACE expression. MI was created by left coronary artery ligation. Fibrosis of the visceral pericardium was induced by pericardiotomy alone. Hearts were studied on postoperative day 3, week 1, 2, 4 and 8. In serial sections of the same heart: immunohistochemistry (antiα-smooth muscle actin antibody and monoclonal ACE antibody, 9B9) was used to detect myofibroblasts and cells expressing ACE, respectively. We found that at sites of MI and pericardial fibrosis, myofibroblasts began to appear on day 3 and became abundant at week 1, 2, 4 and remained in these repairing sites for at least 8 weeks. Myofibroblasts at sites of MI and pericardial fibrosis are positively labeled by ACE antibody. Thus in these models of tissue repair involving either MI or pericardial fibrosis, myofibroblasts are associated with ACE expression. These findings suggest that myofibroblast ACE may play a role in the fibrogenic response of tissue repair in the rat myocardium by regulating local concentrations of substances involved in healing and matrix remodeling.Journal of Molecular and Cellular Cardiology 06/1996; · 5.15 Impact Factor
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ABSTRACT: We have identified a member of the VEGF family by computer-based homology searching and have designated it VEGF-D. VEGF-D is most closely related to VEGF-C by virtue of the presence of N- and C-terminal extensions that are not found in other VEGF family members. In adult human tissues, VEGF-D mRNA is most abundant in heart, lung, skeletal muscle, colon, and small intestine. Analyses of VEGF-D receptor specificity revealed that VEGF-D is a ligand for both VEGF receptors (VEGFRs) VEGFR-2 (Flk1) and VEGFR-3 (Flt4) and can activate these receptors. However. VEGF-D does not bind to VEGFR-1. Expression of a truncated derivative of VEGF-D demonstrated that the receptor-binding capacities reside in the portion of the molecule that is most closely related in primary structure to other VEGF family members and that corresponds to the mature form of VEGF-C. In addition, VEGF-D is a mitogen for endothelial cells. The structural and functional similarities between VEGF-D and VEGF-C define a subfamily of the VEGFs.Proceedings of the National Academy of Sciences 02/1998; 95(2):548-53. · 9.81 Impact Factor