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Expression of the AT2 receptor developmentally programs extracellular signal-regulated kinase activity and influences fetal vascular growth.

Publication ,  Journal Article
Akishita, M; Ito, M; Lehtonen, JY; Daviet, L; Dzau, VJ; Horiuchi, M
Published in: J Clin Invest
January 1999

Angiotensin II type 2 (AT2) receptor is abundantly expressed in vascular smooth muscle cells (VSMC) of the fetal vasculature during late gestation (embryonic day 15-20), during which the blood vessels undergo remodeling. To examine directly the influence of AT2 receptor expression in the developmental biology of VSMC, we studied cultures of VSMC from fetal and postnatal wild-type (Agtr2(+)) and AT2 receptor null (Agtr2(-)) mice. Consistent with in vivo data, AT2 receptor binding in cultured Agtr2(+) VSMC increased by age, peaking at embryonic day 20, and decreased dramatically after birth. Angiotensin II-induced growth in Agtr2(+) VSMC (embryonic day 20) was increased by the AT2 receptor blocker PD123319, indicating that the AT2 receptors are functional and exert an antigrowth effect in Agtr2(+) VSMC. Growth of VSMC in response to serum decreased age dependently and was higher in Agtr2(-) than in Agtr2(+), inversely correlating with AT2 receptor expression. However, serum-induced growth in Agtr2(+) and Agtr2(-) VSMC and the exaggerated Agtr2(-) VSMC growth was maintained even in the presence of PD123319 or losartan, an AT1 receptor blocker. Moreover, Agtr2(-) VSMC showed greater growth responses to platelet-derived growth factor and basic fibroblast growth factor, indicating that Agtr2(-) cells exhibit a generalized exaggerated growth phenotype. We studied the mechanism responsible for this phenotype and observed that extracellular signal-regulated kinase (ERK) activity was higher in Agtr2(-) VSMC at baseline and also in response to serum. ERK kinase inhibitor PD98059 inhibited both growth and ERK phosphorylation dose-dependently, while the regression lines between growth and ERK phosphorylation were identical in Agtr2(+) and Agtr2(-) VSMC, suggesting that increased ERK activity in Agtr2(-) VSMC is pivotal in the growth enhancement. Furthermore, the difference in ERK phosphorylation between Agtr2(+) and Agtr2(-) was abolished by vanadate but not by okadaic acid, implicating tyrosine phosphatase in the difference in ERK activity. These results suggest that the AT2 receptor expression during the fetal vasculogenesis influences the growth phenotype of VSMC via the modulation of ERK cascade.

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Published In

J Clin Invest

DOI

ISSN

0021-9738

Publication Date

January 1999

Volume

103

Issue

1

Start / End Page

63 / 71

Location

United States

Related Subject Headings

  • Vanadates
  • Receptors, Angiotensin
  • Pyridines
  • Protein Binding
  • Phosphorylation
  • Phosphoproteins
  • Okadaic Acid
  • Muscle, Smooth, Vascular
  • Muscle Development
  • Mice, Knockout
 

Citation

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Akishita, M., Ito, M., Lehtonen, J. Y., Daviet, L., Dzau, V. J., & Horiuchi, M. (1999). Expression of the AT2 receptor developmentally programs extracellular signal-regulated kinase activity and influences fetal vascular growth. J Clin Invest, 103(1), 63–71. https://doi.org/10.1172/JCI5182
Akishita, M., M. Ito, J. Y. Lehtonen, L. Daviet, V. J. Dzau, and M. Horiuchi. “Expression of the AT2 receptor developmentally programs extracellular signal-regulated kinase activity and influences fetal vascular growth.J Clin Invest 103, no. 1 (January 1999): 63–71. https://doi.org/10.1172/JCI5182.
Akishita M, Ito M, Lehtonen JY, Daviet L, Dzau VJ, Horiuchi M. Expression of the AT2 receptor developmentally programs extracellular signal-regulated kinase activity and influences fetal vascular growth. J Clin Invest. 1999 Jan;103(1):63–71.
Akishita, M., et al. “Expression of the AT2 receptor developmentally programs extracellular signal-regulated kinase activity and influences fetal vascular growth.J Clin Invest, vol. 103, no. 1, Jan. 1999, pp. 63–71. Pubmed, doi:10.1172/JCI5182.
Akishita M, Ito M, Lehtonen JY, Daviet L, Dzau VJ, Horiuchi M. Expression of the AT2 receptor developmentally programs extracellular signal-regulated kinase activity and influences fetal vascular growth. J Clin Invest. 1999 Jan;103(1):63–71.

Published In

J Clin Invest

DOI

ISSN

0021-9738

Publication Date

January 1999

Volume

103

Issue

1

Start / End Page

63 / 71

Location

United States

Related Subject Headings

  • Vanadates
  • Receptors, Angiotensin
  • Pyridines
  • Protein Binding
  • Phosphorylation
  • Phosphoproteins
  • Okadaic Acid
  • Muscle, Smooth, Vascular
  • Muscle Development
  • Mice, Knockout