High glucose and endothelial cell growth: novel effects independent of autocrine TGF- 1 and hyperosmolarity

McGinn, S., P. Poronnik, M. King, E. D. M. Gallery, and C. A. Pollock. High glucose and endothelial cell growth: novel effects independent of autocrine TGF1 and hyperosmolarity. Am J Physiol Cell Physiol 284: C1374–C1386, 2003.FirstpublishedJanuary22,2003;10.1152/ajpcell.00466. 2002.—Human endothelial cells were exposed to 5 mM glucose (control), 25 mM (high) glucose, or osmotic control for 72 h. TGF1 production, cell growth, death, and cell cycle progression, and the effects of TGF1 and TGFneutralization on these parameters were studied. High glucose and hyperosmolarity increased endothelial TGF1 secretion (P 0.0001) and bioactivity (P 0.0001). However, high glucose had a greater effect on reducing endothelial cell number (P 0.001) and increasing cellular protein content (P 0.001) than the osmotic control. TGFantibody only reversed the antiproliferative and hypertrophic effects of high glucose. High glucose altered cell cycle progression and cyclin-dependent kinase inhibitor expression independently of hyperosmolarity. High glucose increased endothelial cell apoptosis (P 0.01), whereas hyperosmolarity induced endothelial cell necrosis (P 0.001). TGFantibody did not reverse the apoptotic effects observed with high glucose. Exogenous TGF1 mimicked the increased S phase delay but not endoreduplication observed with high glucose. High glucose altered endothelial cell growth, apoptosis, and cell cycle progression. These growth effects occurred principally via a TGF1 autocrine pathway. In contrast, apoptosis and endoreduplication occurred independently of this cytokine and hyperosmolarity.