Vascular endothelial growth factor induced functional and morphologic signs of endothelial dysfunction in isolated arteries from normal pregnant women.
OBJECTIVE
The purpose of this study was to determine the effects of vascular endothelial growth factor on basal tone, endothelium-dependent dilatation, permeability, and morphologic features of endothelium in isolated arteries from normal pregnant women. We hypothesized that vascular endothelial growth factor might induce signs of endothelial dysfunction.


METHODS
Arteries (approximately 200 microm) were dissected from subcutaneous fat biopsy specimens that were obtained at cesarean delivery and mounted on a pressure arteriograph. Changes in basal tone, dilatation to bradykinin (1 nmol/L to 3 micromol/L) before, during, and after 3 hours of incubation with vascular endothelial growth factor (0.5 or 1 nmol/L), vascular endothelial growth factor (0.5 nmol/L) plus bosentan (a nonselective endothelin receptor A and B antagonist, 1 micromol/L), or vehicle were compared. Scanning electron microscopy was applied for endothelial morphologic features. Permeability to Evans blue dye was evaluated in arteries after incubation with vascular endothelial growth factor, vascular endothelial growth factor plus angiopoietin-1, or vehicle, and in arteries that were obtained from women with preeclampsia.


RESULTS
Basal tone was higher after 60 minutes of incubation with vascular endothelial growth factor (0.5 nmol/L) compared with vehicle (29% +/- 5% [n = 10] vs 10% +/- 4% [n = 7], P =.006). Combination of vascular endothelial growth factor with bosentan failed to increase the tone (n = 4). Bradykinin-mediated dilatation was impaired in arteries that were incubated with vascular endothelial growth factor 0.5 nmol/L (max dilatation: 287% +/- 16% vs 160% +/- 23% [n = 10], P =.0001) or vascular endothelial growth factor 1 nmol/L (max dilatation: 207% +/- 21% vs 88% +/- 4% [n = 3], P =.003). Bradykinin-mediated dilatation was similar after incubation with vehicle (n = 7) or the combination of vascular endothelial growth factor plus bosentan (n = 4). Evans blue dye staining was higher after incubation with vascular endothelial growth factor but was reversed by the addition of angiopoietin-1. Scanning electron microscopy demonstrated the development of intercellular gaps.


CONCLUSIONS
Vascular endothelial growth factor impaired bradykinin-mediated dilatation and enhanced basal tone and permeability. This might indicate a potential role for vascular endothelial growth factor in the development of endothelial dysfunction in pregnancy. Angiopoietin-1 inhibited the vascular endothelial growth factor-induced vascular leakage, which may have therapeutic implications in preeclampsia.
Svedas
Eimantas
E
Section for Obstetrics and Gynecology, Department of Clinical Science, Karolinska Institute, Huddinge University Hospital, Stockholm, Sweden.
Islam
Khalid B
KB
Nisell
Henry
H
Kublickiene
Karolina R
KR
D000273:Adipose Tissue / Q000098:blood supply; D000328:Adult; D043925:Angiogenesis Inducing Agents / Q000494:pharmacology; D042683:Angiopoietin-1; D001158:Arteries; D000077300:Bosentan; D001920:Bradykinin / Q000494:pharmacology; D002199:Capillary Permeability / Q000187:drug effects; D016228:Endothelial Growth Factors / Q000494:pharmacology*; D065128:Endothelin Receptor Antagonists; D004730:Endothelium, Vascular / Q000503:physiopathology* / Q000648:ultrastructure; D005260:Female; D017629:Gap Junctions / Q000648:ultrastructure; D006801:Humans; D066298:In Vitro Techniques; D036341:Intercellular Signaling Peptides and Proteins / Q000494:pharmacology*; D007700:Kinetics; D008222:Lymphokines / Q000494:pharmacology*; D008562:Membrane Glycoproteins / Q000494:pharmacology; D008855:Microscopy, Electron, Scanning; D011225:Pre-Eclampsia / Q000473:pathology / Q000503:physiopathology; D011247:Pregnancy; D011994:Recombinant Proteins / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D014664:Vasodilation / Q000187:drug effects
D043925:Angiogenesis Inducing Agents; D042683:Angiopoietin-1; D016228:Endothelial Growth Factors; D065128:Endothelin Receptor Antagonists; D036341:Intercellular Signaling Peptides and Proteins; D008222:Lymphokines; D008562:Membrane Glycoproteins; D011994:Recombinant Proteins; D013449:Sulfonamides; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D000077300:Bosentan; D001920:Bradykinin