Autocrine effects of endothelin on in vitro proliferation of vascular smooth muscle cells from spontaneously hypertensive and normotensive rats.
According to previous studies, endothelin-1 (ET-1) is the most potent growth factor in the regulation of vascular smooth muscle cell (VSMC) proliferation in spontaneously hypertensive rats (SHR). To evaluate if the dominant effect of ET-1-induced VSMC proliferation is achieved by autocrine regulation, aortic smooth muscle cells from four-week-old SHR and WKY (Wistar-Kyoto) rats were cultured in 24-well dishes, and the effects of ET-1 on VSMC proliferation were determined by (a) 3H-thymidine incorporation assays with different ET-1 blocking treatments, including a specific anti-ET-1 antibody; BQ-123, an ETA receptor blocker; and BQ-788, an ETB receptor blocker; and (b) examining the ET-1 blockade on the effects of treatment with other growth factors, including thrombin and angiotension II (AT-II). These results demonstrated that the anti-ET-1 antibody, BQ-123, BQ-788, and BQ-123 plus BQ-788 all caused dose-dependent inhibition of proliferation. A 90% inhibitory effect was observed at the maximum doses used except for BQ-123. The ET-1 receptor blockers inhibited thrombin-induced VSMC growth; however, they did not efficiently inhibit AT-II-induced VSMC growth. These results indicate that the autocrine effects of ET-1 play a predominant role in the proliferation of VSMCs from SHR and WKY rats. They also suggest that thrombin-induced VSMC growth is mediated by the autocrine effects of ET-1, and angiotensin II-induced VSMC growth is mediated by other signal pathways.
Lu
Mei-Hua
MH
Department of Biology and Anatomy, National Defense Medical Center, Taipei, Taiwan, Republic of China. meihua@ndmctsgh.edu.tw
Chao
Chung-Faye
CF
Tsai
Shih-Hung
SH
Chen
Jang-Yi
JY
Chang
Li-Tze
LT
D000804:Angiotensin II / Q000008:administration & dosage; D000818:Animals; D000959:Antihypertensive Agents / Q000008:administration & dosage; D001013:Aorta, Thoracic / Q000166:cytology; D019898:Autocrine Communication / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000008:administration & dosage*; D006490:Hemostatics / Q000008:administration & dosage; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000166:cytology*; D032389:Myocytes, Smooth Muscle / Q000187:drug effects*; D009842:Oligopeptides / Q000008:administration & dosage / Q000037:antagonists & inhibitors; D010456:Peptides, Cyclic / Q000008:administration & dosage / Q000037:antagonists & inhibitors; D010880:Piperidines / Q000008:administration & dosage / Q000037:antagonists & inhibitors; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D017466:Receptors, Endothelin / Q000008:administration & dosage; D015398:Signal Transduction / Q000187:drug effects; D013917:Thrombin / Q000008:administration & dosage; D014662:Vasoconstrictor Agents / Q000008:administration & dosage
D000959:Antihypertensive Agents; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D006490:Hemostatics; D009842:Oligopeptides; D010456:Peptides, Cyclic; D010880:Piperidines; D017466:Receptors, Endothelin; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; C086539:BQ 788; D013917:Thrombin; C072247:cyclo(Trp-Asp-Pro-Val-Leu)