Vascular endothelial growth factor-D is overexpressed in human cardiac allograft vasculopathy and diabetic atherosclerosis and induces endothelial permeability to low-density lipoproteins in vitro.

TitleVascular endothelial growth factor-D is overexpressed in human cardiac allograft vasculopathy and diabetic atherosclerosis and induces endothelial permeability to low-density lipoproteins in vitro.
Publication TypeJournal Article
Year of Publication2011
AuthorsWong, BW, Wong, D, Luo, H, McManus, BM
JournalJ Heart Lung Transplant
Volume30
Issue8
Pagination955-62
Date Published2011 Aug
ISSN1557-3117
KeywordsAdolescent, Adult, Arterioles, Atherosclerosis, Cell Membrane Permeability, Cells, Cultured, Coronary Artery Disease, Coronary Vessels, Diabetic Angiopathies, Endothelium, Vascular, Female, Humans, In Vitro Techniques, Lipoproteins, LDL, Male, Mitogen-Activated Protein Kinase 1, Mitogen-Activated Protein Kinase 3, Tight Junctions, Tunica Intima, Tunica Media, Vascular Endothelial Growth Factor D, Young Adult
Abstract

BACKGROUND: Vascular endothelial growth factor (VEGF)-D is a member of the VEGF family, which can induce angiogenesis and lymphangiogenesis. We have previously demonstrated a role for VEGF-A in cardiac allograft vasculopathy (CAV). Our experiments profile the expression and localization of VEGF-D in human native atherosclerosis (NA), diabetes mellitus with atherosclerosis (DM) and CAV, and we investigate its ability to induce low-density lipoprotein (LDL) permeability in human cardiac microvascular endothelial cells (HCMEC).

METHODS: VEGF-D mRNA and protein expression was characterized in coronary arteries and intramyocardial arterioles in NA, DM and CAV using in situ hybridization and immunohistochemical staining. Transendothelial electrical resistance (TER) measurements and immunocytochemical staining for platelet and endothelial cell adhesion molecule-1 and zonula occludens-1 were used to assess endothelial barrier and tight junctional integrity. LDL permeability in response to treatment with VEGF-D was measured using fluorometry in confluent HCMEC.

RESULTS: Image quantitation demonstrated significant increases in VEGF-D immunoreactivity in the media of coronary arteries and intramyocardial arterioles of CAV cases, and in the intima and media of coronary arteries of DM cases. Treatment with VEGF-D, in vitro, significantly increased LDL passage through HCMEC monolayers. In conjunction, treatment with VEGF-D significantly decreased TER measurements 2 hours post-treatment and induced the formation of intercellular gaps through an extracellular signal-regulated kinase 1/2 (ERK1/2)-dependent pathway.

CONCLUSIONS: VEGF-D is overexpressed in the arteries of CAV and DM cases. Treatment with VEGF-D can disrupt HCMEC tight junctions, resulting in the formation of intercellular gaps, and can also significantly increase LDL permeability through confluent monolayers.

DOI10.1016/j.healun.2011.04.007
Alternate JournalJ. Heart Lung Transplant.
PubMed ID21620738
Grant List / / Canadian Institutes of Health Research / Canada