Macrovascular and microvascular endothelium during long-term hypoxia: alterations in cell growth, monolayer permeability, and cell surface coagulant properties.
In bovine aortic or capillary endothelial cells (ECs) incubated under hypoxic conditions, cell growth was slowed in a dose-dependent manner at lower oxygen concentrations, as progression into S phase from G1 was inhibited, concomitant with decreased thymidine kinase activity. Monolayers grown to confluence in ambient air, wounded, and then transferred to hypoxia showed decreased ability to repair the wound, as a result of both decreased motility and cell division. Hypoxic ECs demonstrated a approximately 3-fold increase in the total number of high-affinity fibroblast growth factor receptors, and levels of endogenous FGF were suppressed. Consistent with the presence of functional FGF receptors, addition of basic FGF overcame, at least in part, hypoxia-mediated suppression of EC growth, and enhanced wound repair in hypoxia, stimulating both motility and cell division. Despite slower growth in hypoxia, ECs could achieve confluence, and the monolayers consisted of larger cells with altered assembly of the actin-based cytoskeleton and small gaps between contiguous cells. The permeability of these hypoxic EC monolayers to macromolecules and lower molecular weight solutes was increased. Cell surface coagulant properties were also perturbed: the anticoagulant cofactor thrombomodulin was suppressed, and a novel Factor X activator appeared on the EC surface. These data indicate that micro- and macrovascular ECs can grow and be maintained at low oxygen tensions, but hypoxic endothelium exhibits a range of altered functional properties which can potentially contribute to the pathogenesis of vascular lesions.
Shreeniwas
R
R
Department of Physiology, College of Physicians and Surgeons, Columbia University New York, New York 10032.
Ogawa
S
S
Cozzolino
F
F
Torcia
G
G
Braunstein
N
N
Butura
C
C
Brett
J
J
Lieberman
H B
HB
Furie
M B
MB
Joseph-Silverstein
J
J
D000818:Animals; D001011:Aorta; D001779:Blood Coagulation Factors / Q000378:metabolism*; D002196:Capillaries; D002417:Cattle; D002455:Cell Division; D015687:Cell Hypoxia / Q000502:physiology*; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000166:cytology / Q000502:physiology*; D016222:Fibroblast Growth Factor 2 / Q000502:physiology; D010539:Permeability; D012038:Regeneration
D001779:Blood Coagulation Factors; D016222:Fibroblast Growth Factor 2