© 2001 by European Society of Cardiology
Copyright © 2000, European Society of Cardiology
Differential regulation of thrombospondin-1 and fibronectin by angiotensin II receptor subtypes in cultured endothelial cells
aInstitute of Pharmacology, Christian-Albrechts-University Kiel, 24105 Kiel, Germany
bKnoll AG, Ludwigshafen, Germany
* Corresponding author jens.fischer{at}pharmakologie.uni-kiel.de
Objectives: Angiotensin II (ANG II) can modulate cellular proliferation in various cell types via AT1 and AT2 receptors. In the present study, we investigated the effect of the angiotensin AT1 and AT2 receptors on DNA-synthesis as well as on the expression of the extracellular matrix (ECM) components, thrombospondin-1 (TSP-1) and fibronectin (FN) in endothelial cells (EC). Methods: The experiments were performed in microvascular EC derived from rat heart (CEC) and macrovascular EC derived from bovine aorta (BAEC). The experiments were performed in cells of the second and third passage and the expression of AT1 and AT2 receptors was verified by binding studies, Northern analysis or RT–PCR. Quiescent rat CEC and BAEC were stimulated to proliferate by the addition of 25 ng/ml bFGF, while ANG II (10–7 M) and the selective ANG II receptor antagonists, Losartan (10–5 M) and PD123177 (10–6 M) or the AT2 agonist, CGP42112A (10–7 M) were added 16 h later. Results: ANG II induced a dose-dependent decrease of DNA-synthesis in BAEC measured by [3H]-thymidine incorporation. This inhibitory effect of ANG II was prevented by the addition of the AT2 receptor antagonist PD123177 (10–6 M), demonstrating, that the inhibition of DNA synthesis is mediated by the AT2 receptor. In the presence of Losartan, stimulation of both, CEC and BAEC, with ANG II resulted in a marked increase of TSP-1 mRNA levels, which was maximal between 3 and 6 h in rat CEC and after 9 h in BAEC. In addition, TSP-1 was clearly induced by the AT2 agonist CGP42112A. In contrast, blockade of the AT2 receptor by the selective AT2 antagonist, PD123177 (10–6 M), resulted in a pronounced down regulation of FN mRNA 9 h after the stimulation. Conclusions: The present results suggest that the ANG II receptor subtype AT2 mediates growth inhibition in macrovascular EC similar to what has been shown before in microvascular rat EC and that AT2 receptors mediates remodeling of the endothelial ECM by upregulation of TSP-1 expression in both macro- and micro-vascular endothelial cells.
KEYWORDS CEC, microvascular endothelial cells from rat heart; BAEC, bovine aortic endothelial cells; ANG II, angiotensin II; AT1 receptor, angiotensin II receptor subtype 1; AT2 receptor, angiotensin II receptor subtype 2; TSP-1, thrombospondin-1; FN, fibronectin; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; PBS, phosphate buffered saline; bFGF, basic fibroblast growth factor; VSMC, vascular smooth muscle cells
1 These authors contributed equally to the research described in this manuscript.
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