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Cardiovascular Research 2001 49(3):681-689; doi:10.1016/S0008-6363(00)00269-8
© 2001 by European Society of Cardiology
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Copyright © 2001, European Society of Cardiology

Thapsigargin inhibits angiogenesis in the rat isolated aorta: studies on the role of intracellular calcium pools

N. Shuklaa, N. Freemana, P. Gadsdonb, G.D. Angelinia and J.Y. Jeremya,*

aDepartment of Anaesthesia and Cardiac Surgery, Bristol Royal Infirmary, University of Bristol, Bristol, UK
bDepartment of Biomedical Sciences, John Moores University of Liverpool, Byrom St., Liverpool, UK

* Corresponding author. Correspondence address: Bristol Heart Institute, Bristol Royal Infirmary, University of Bristol, Bristol BS2 8HW UK. Tel.: +44-0117-928-3154; fax: +44-0117-929-9737 j.y.jeremy{at}bristol.ac.uk

Objective: Since the role of Ca2+ in angiogenesis is not fully understood, we investigated the effect of thapsigargin (TG: depletes intracellular Ca2+ pools) and other Ca2+ modulators [ionomycin, calcium ionophore A23187 [GenBank] and dibutyrylhydroquinone (DBHQ)] on in vitro angiogenesis by rat aortic rings. Methods: Aortae from Sprague–Dawley rats were cut into 2-mm rings, embedded in a fibrin clot and cultured for 15 days in serum-free medium containing drugs and the microvessels counted. Rings were also pre-treated with TG and Ca2+ modulators for 1 h prior to embedding and culture. Viability was examined by the measurement of lactic acid dehydrogenase release. Rings were also treated with hydrocortisone and lavendustin A (a tyrosine kinase inhibitor), as positive controls. The effect of TG on the proliferation and migration of human umbilical artery endothelial cells (HUVECs) was studied in parallel. Results: TG significantly inhibited microvessel formation and HUVEC proliferation and migration in a dose-dependent manner, all at <10 nmol/l, without affecting viability. In contrast, ionomycin, A23187 [GenBank] and DBHQ were cytotoxic at inhibitory concentrations. Continual exposure to hydrocortisone and lavendusin A also inhibited angiogenesis without affecting viability. Conclusion: Since low concentrations of TG deplete intracellular Ca2+ stores, it is concluded that these pools play a central role in mediating angiogenesis.

KEYWORDS Angiogenesis; Calcium (cellular)


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