Increased vascular endothelial growth factor expression in human hearts with microvascular fibrin.
We have shown that microvascular changes that promote fibrin deposition in human cardiac allografts adversely affect clinical outcome. However, some allografts exhibit phenotypic changes in capillaries following the deposition of fibrin, which subsequently provide a significant survival advantage. The mechanism(s) involved in these capillary changes is(are) unknown. Similarly, although we have shown a significant temporal relationship between microvascular fibrin deposition and vascular endothelial growth factor (VEGF) immunoreactivity in cardiac allografts, the cellular source and relative changes in VEGF gene expression under these conditions are not known. Using immunocytochemical techniques, biopsies devoid of fibrin deposition lacked detectable VEGF immunoreactivity, whereas biopsies with fibrin deposition showed VEGF immunoreactivity in cardiocytes, interstitium, and some microvessels. By in situ hybridization, biopsies without microvascular fibrin deposition showed faint VEGF hybridization signals confined primarily to cardiocytes. In biopsies with fibrin deposition, strong VEGF hybridization signals were detected in cardiocytes, arteriolar smooth muscle cells were occasionally labeled, and endothelial cells were rarely labeled. By quantitative RT-PCR, biopsies with fibrin deposition (n=5) relatively expressed approximately three-fold more VEGF mRNA than biopsies without fibrin deposition (n=5 P=0.02). Serum VEGF titers also were greater (P=0.01) in recipients with fibrin deposition (372.9+/-66.7 pg/ml n=18) compared to recipients without fibrin deposition (172.1+/-25.0 pg/ml n=16). Collectively, these results support the hypothesis that increased myocyte-derived VEGF production following microvascular fibrin deposition in transplanted human hearts may act in a paracrine manner to promote activational and phenotypic changes in capillaries that provide a survival advantage for the allografts.
Torry
R J
RJ
College of Pharmacy and Health Sciences, Drake University, Des Moines, IA 50311, USA. Ron.Torry@drake.edu
Bai
L
L
Miller
S J
SJ
Labarrere
C A
CA
Nelson
D
D
Torry
D S
DS
D001706:Biopsy; D002196:Capillaries / Q000473:pathology*; D015687:Cell Hypoxia; D003097:Collateral Circulation; D004058:Diffusion; D004699:Endocardium / Q000378:metabolism / Q000473:pathology*; D016228:Endothelial Growth Factors / Q000096:biosynthesis* / Q000097:blood / Q000235:genetics; D004797:Enzyme-Linked Immunosorbent Assay; D005337:Fibrin / Q000032:analysis*; D005786:Gene Expression Regulation; D006085:Graft Survival; D016027:Heart Transplantation / Q000473:pathology*; D006801:Humans; D017403:In Situ Hybridization; D008222:Lymphokines / Q000096:biosynthesis* / Q000097:blood / Q000235:genetics; D017202:Myocardial Ischemia / Q000473:pathology*; D018919:Neovascularization, Physiologic / Q000235:genetics; D020033:Protein Isoforms / Q000096:biosynthesis* / Q000097:blood / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D016228:Endothelial Growth Factors; D008222:Lymphokines; D020033:Protein Isoforms; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D005337:Fibrin