Abstract
Angiotensin-(1–7) is increased in the circulation during human pregnancy, but its functional role is unknown. Recent studies suggested that it opposes angiotensin II mediated vascular growth. Because angiogenesis is critical to normal embryonic development during human pregnancy, this study assessed the in vitro effects of angiotensin-(1–7) on human umbilical vein endothelial cell tube formation. The blocking effects of the angiotensin-(1–7) receptor antagonist, D-[Alanine7]-Ang-(1–7), and angiotensin II receptor AT1 and AT2 antagonists, losartan and PD123319, on tube formation were measured by counting tube branch points. Human umbilical vein endothelial cells were cultured in EGM-2 medium and treated with angiotensin-(1–7) (0.17 nM–17 μM) for 18 h. Angiotensin-(1–7) inhibited tube formation by 24% (P < 0.01) at all doses tested. Treatment with 1.7 μM angiotensin-(1–7) plus 17 μM D-[Alanine7]-Ang-(1–7) resulted in the reversal of angiotensin-(1–7) mediated inhibition of tube formation (P < 0.05). Losartan (17 μM) also reversed the angiotensin-(1–7) mediated inhibition of tube formation (P < 0.05). Tube formation was unaffected by PD123319. These results suggest that angiotensin-(1–7) has an anti-angiogenic effect on human umbilical vein endothelial cells through a unique AT1–7 receptor that is sensitive to losartan, indicating that angiotensin-(1–7) may play an important role in the regulation of vascular growth in the placenta during pregnancy.
Similar content being viewed by others
References
A. Nasjletti, G.M.C. Masson, Circ. Res. [Suppl. II] 30, 187–202 (1972)
D.A. Tewksbury, in Angiotensinogen – Biochemistry and Molecular Biology, ed. by J.H. Laragh B.M. Brenner (Raven Press, New York, 1990), pp. 1197–1216
Y. Chen, A.J. Naftilan, S. Oparil, Hypertension 19, 456–463 (1992)
S. Rubattu, F.W. Quimby, J.E. Sealey, J. Hypertens. 9, 525–535 (1991)
M.A. Brown, J. Wang, J.A. Whitworth, Clin. Exp. Hypertens. 19, 713–726 (1997)
P.N. Baker, F.B. Pipkin, E.M. Symonds, Clin. Sci. 79, 403–408 (1990)
D.C. Merrill, M. Karoly, K. Chen, C.M. Ferrario, K.B. Brosnihan, Endocrine 18, 239–245 (2002)
G. Valdes, A.M. Germain, J. Corthorn, C. Berrios, A.C. Foradori, C.M. Ferrario, K.B. Brosnihan, Endocrine 16, 117–122 (2001)
K.B. Brosnihan, R.A.S. Santos, C.H. Block, M.T. Schiavone, W.R. Welches, M.C. Chappell, M.C. Khosla, L.J. Greene C.M. Ferrario, Ther. Res. 9, 48–59 (1988)
C.M. Ferrario, M.C. Chappell, Curr. Opin. Cardiol. 9, 520–526 (1994)
P. Janiak, A. Pillon, J.F. Prost, J.P. Vilaine, Hypertension 20, 737–745 (1992)
T. Csikos, O. Chung, T. Unger, J. Hum. Hypertens. 12, 311–318 (1998)
R.L. Haberl, F. Anneser, A. Villringer, K.M. Einhaupl, Am. J. Physiol. 258, H1840–H1846 (1990)
S. Arima, Y. Endo, H. Yaoita, K. Omata, S. Ogawa, K. Tsunoda, M. Abe, K. Takeuchi, J. Clin. Invest. 100, 2816–2323 (1997)
A. Abbas, G. Gorelik, L.A. Carbini, A.G. Scicli, Hypertension 30, 217–221 (1997)
L.M.O. Botelho, L.A. Neves, C.H. Block, M.C. Khosla, R.A.S. Santos, Hypertension 21, 603 (abstract) (1993)
F.J. Salazar, M.T. Llinas, NIPS 11, 62–67 (1996)
C.V. Lima, R.D. Paula, F.L. Resende, M.C. Khosla, R.A.S. Santos, Hypertension 30, 542–548 (1997)
R.A.S. Santos, A.C. Simoes e Silva, C. Maric, D.M. Silva, R.P. Machado, I. de Bul, S. Heringer-Walther, S.V. Pinheiro, M.T. Lopes, M. Bader, E.P. Mendes, V.S. Lemos, M.J. Campagnole-Santos, H.-P. Schultheiss, R. Speth, T. Walther, Proc. Natl. Acad. Sci. USA 100, 8258–8263 (2003)
R.A. Santos, A.C.S. Silva, C. Maric, R. Speth, R.P. Machado, S.V. Pinheiro, M.T. Lopes, E.P. Mendes, M. Bader, H.-P. Schultheiss, M.J. Campagnole-Santos, T. Walther, Hypertension 40, 387 (2002)
G. Valdes, L.A. Neves, L. Anton, J. Corthorn, C. Chacon, A.M. Germain, D.C. Merrill, C.M. Ferrario, R. Sarao, J. Penninger, K.B. Brosnihan, Placenta 27, 200–207 (2006)
L. Anton, D.C. Merrill, D. Diz, L.A.A. Neves, K. Stovall, P.E. Gallagher, C. Moorefield, G. Gruver, C.M. Ferrario, K.B. Brosnihan, Hypertension 50, e79 (abstract) (2007)
B. Williams, Miner. Electrolyte. Metab. 24, 400–405 (1998)
A. Otani, H. Takagi, K. Suzuma, Y. Honda, Circ. Res. 82, 619–628 (1998)
C.C. Chua, R.C. Hamdy, B.H. Chua, Biochim. Biophys. Acta. 1401, 187–194 (1998)
S. Fujiyama, H. Matsubara, Y. Nozawa, K. Maruyama, Y. Mori, Y. Tsutsumi, H. Masaki, Y. Uchiyama, Y. Koyama, A. Nose, O. Iba, E. Tateishi, N. Ogata, N. Jyo, S. Higashiyama, T. Iwasaka, Circ. Res. 88, 22–29 (2001)
S.L. Amaral, J.R. Linderman, M.M. Morse, A.S. Greene, Microcirculation 8, 57–67 (2001)
E.J. Freeman, G.M. Chisolm, C.M. Ferrario, E.A. Tallant, Hypertension 28, 104–108 (1996)
W. Zeng, M.A. Hong, L. Wang, Chin. J. Geriatr. Cardiovasc. Cerebrovasc. Dis. 3, 107–109 (2001)
R.D. Machado, R.A. Santos, S.P. Andrade, Am. J. Physiol. Regul. Integr. Comp. Physiol. 280, R994–R1000 (2001)
R.D. Machado, R.A. Santos, S.P. Andrade, Life Sci. 66, 67–76 (2000)
W.O. Sampaio, R.A. Souza dos Santos, R. Faria-Silva, L.T. da Mata Machado, E.L. Schiffrin, R.M. Touyz, Hypertension 49, 185–192 (2007)
M. Iwata, R.T. Cowling, D. Gurantz, C. Moore, S. Zhang, J.X. Yuan, B.H. Greenberg, Am. J. Physiol. Heart Circ. Physiol. 289, H2356–H2363 (2005)
E.A. Tallant, M.A. Clark, Hypertension 42, 574–579 (2003)
L. Fernandes, Z.B. Fortes, D. Nigro, R.C. Tostes, R.A. Santos, M.H.C. Carvalho, Hypertension 37, 703–709 (2001)
K.B. Brosnihan, P. Li, C.M. Ferrario, Hypertension 27, 523–528 (1996)
C.M. Ferrario, M.C. Chappell, E.A. Tallant, K.B. Brosnihan, D.I. Diz, Hypertension 30, 535–541 (1997)
I. Porsti, A.T. Bara, R. Busse, M. Hecker, Br. J. Pharmacol. 111, 652–654 (1994)
E.A. Tallant, X. Lu, R.B. Weiss, M.C. Chappell, C.M. Ferrario, Hypertension 29, 388–392 (1997)
N.C. Baracho, A. Simoes-e-Silva, M.C. Khosla, R.A. Santos, Braz. J. Med. Biol. Res. 31, 1221–1227 (1998)
C.J. Chung, M.C. Chappell, M.F. Callahan, T.M. Coffman, A.J. Allred, D.I. Diz, Faseb J. 15, A778 (abstract) (2001)
P.D. Potts, J. Horiuchi, M.J. Coleman, R.A. Dampney, Brain Res. 877, 58–64 (2000)
L.A. Neves, D.B. Averill, C.M. Ferrario, M.C. Chappell, J.L. Aschner, M.P. Walkup, K.B. Brosnihan, Peptides 24, 455–462 (2003)
P.D. Potts, A.M. Allen, J. Horiuchi, R.A. Dampney, Am. J. Physiol. Regul. Integr. Comp. Physiol. 279, R1392–R1402 (2000)
B.P. Rowe, D.L. Saylor, R.C. Speth, D.R. Absher, Regul. Pept. 56, 139–146 (1995)
C. Emanueli, M.B. Salis, T. Stacca, A. Pinna, L. Gaspa, P. Madeddu, P. Maddeddu, Br. J. Pharmacol. 135, 87–92 (2002)
D.H. Munzenmaier, A.S. Greene, Hypertension 27, 760–765 (1996)
K. Sasaki, T. Murohara, H. Ikeda, T. Sugaya, T. Shimada, S. Shintani, T. Imaizumi, J. Clin. Invest. 109, 603–611 (2002)
H. Toko, Y. Zou, T. Minamino, M. Masaya, M. Harada, T. Nagai, T. Sugaya, F. Terasaki, Y. Kitaura, I. Komuro, Arterioscler. Thromb. Vasc. Biol. 24, 664–670 (2004)
M. Stoll, U.M. Steckelings, M.K. Paul, S.P. Bottari, R. Metzger, T. Unger, J. Clin. Invest. 95, 651–657 (1995)
M. Nakajima, H.G. Hutchinson, M. Fujinaga, W. Hayashida, R. Morishnita, L. Zhange, M. Horiuchi, R.E. Pratt, V.J. Dzau, Proc. Natl. Acad. Sci. USA 92, 10663–10667 (1995)
M. Akishita, M. Ito, J.Y. Lehtonen, L. Daviet, V.J. Dzau, M. Horiuchi, J. Clin. Invest. 103, 63–71 (1999)
M.C. Chappell, D.W. Jacobsen, E.A. Tallant, Peptides 16, 741–747 (1995)
M. Ito, A. Itakura, Y. Ohno, M. Nomura, T. Senga, T. Nagasaka, S. Mizutani, J. Clin. Endocrinol. Metab. 87, 1871–1878 (2002)
X. Li, M. Shams, J. Zhu, A. Khalig, M. Wilkes, M. Whittle, N. Barnes, A. Ahmed, J. Clin. Invest. 101, 442–454 (1998)
A.C. Cooper, G. Robinson, G.P. Vinson, W.T. Cheung, P.F. Broughton, Hypertension 32, 687 (1998)
L.A.A. Neves, A.F. Williams, D.B. Averill, C.M. Ferrario, M.P. Walkup, K.B. Brosnihan, Endocrinology 14, 3338–3343 (2003)
Acknowledgements
The authors gratefully acknowledge the technical support of David Sane, MD for his assistance in setting up the in vitro angiogenesis assay. This work was supported in part by grants from the National Institutes of Health, NHLBI-P01 HL58952 and HL67363, and the American Heart Association mid-Atlantic region (AHA0515221U). The authors gratefully acknowledge grant support in part provided by Unifi, In. Greensboro, NC and Farley-Hudson Foundation, Jackonville, NC.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Anton, L., Merrill, D.C., Neves, L.A.A. et al. Angiotensin-(1–7) inhibits in vitro endothelial cell tube formation in human umbilical vein endothelial cells through the AT1–7 receptor. Endocr 32, 212–218 (2007). https://doi.org/10.1007/s12020-007-9022-1
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12020-007-9022-1