Published online before print August 2, 2007, doi: 10.1161/CIRCRESAHA.107.151563
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Submitted on March 2, 2007
Revised on July 20, 2007
Accepted on July 24, 2007
Upregulation of Soluble Vascular Endothelial Growth Factor Receptor 1 Contributes to Angiogenesis Defects in the Placenta of 
2B-Adrenoceptor–Deficient Mice
Verena Muthig ;
From the Institute of Experimental and Clinical Pharmacology (V.M., R.G., M.H., M.P., L.H.), University of Freiburg, Germany; Institute of Cell Biology (M.P.), Duke University Medical Center, Durham, NC; European Molecular Biology Laboratory (T.I.), Heidelberg, Germany; and Department of Physiological Chemistry (M.G.), Biocenter, University of Würzburg, Germany.
* To whom correspondence should be addressed. E-mail: lutz.hein{at}pharmakol.uni-freiburg.de.
2-adrenoceptors are essential presynaptic regulators of norepinephrine release from sympathetic nerves. Previous studies in mice with targeted deletions in the 3 2-adrenoceptor genes have indicated that these receptors are essential for embryonic development. In the present study, we searched for the 2-adrenoceptor subtype(s) involved in placental development and its molecular mechanism using mice carrying targeted deletions in 2-adrenoceptor genes. Congenic 2B-adrenoceptor–deficient mice (Adra2b-/-) developed a defect in fetal and maternal vessel formation in the placenta labyrinth at embryonic day 10.5. This defect was accompanied by reduced endothelial cell proliferation and decreased extracellular signal-regulated kinase 1/2 phosphorylation levels in Adra2b-/- as compared with Adra2b+/+ placentae. Microarray analysis of wild-type and mutant placentae (maternal genotype Adra2b+/-) revealed 179 genes, which were significantly up- or downregulated >1.5-fold in 2B-deficient placentae. The type 1 receptor for vascular endothelial growth factor (Flt1), which is coexpressed with 2B-adrenoceptors in spongiotrophoblast and giant cells of the placenta, was found to be 2.3-fold upregulated in 2B-deficient placentae. Neutralization of Flt1 and its soluble splice variant sFlt1 by a specific antibody in vivo prevented the vascular defect in 2B-deficient placentae at embryonic day 10.5. Thus, 2B-adrenoceptors are essential to suppress antiangiogenic (s)Flt1 in spongiotrophoblasts to control the coordinated formation of a vascular labyrinth of fetal and maternal blood vessels in the murine placenta during development.
Key words: adrenergic receptors • angiogenesis • gene-targeted mice • vascular endothelial growth factor
Related Article:
-
Sympathetic Control of VEGF Angiogenic Signaling: Dual Regulations by 2-Adrenoceptor Activation?
- Yuichi Hattori, Seiji Yamamoto, and Naoyuki Matsuda
Circ. Res. 2007 101: 642-644.[Extract] [Full Text] [PDF]
This article has been cited by other articles:
 |
|
 |
|
  C. Rampon, S. Bouillot, A. Climescu-Haulica, M.-H. Prandini, F. Cand, Y. Vandenbrouck, and P. Huber Protocadherin 12 deficiency alters morphogenesis and transcriptional profile of the placenta Physiol Genomics, July 1, 2008; 34(2): 193 - 204. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Hattori, S. Yamamoto, and N. Matsuda Sympathetic Control of VEGF Angiogenic Signaling: Dual Regulations by {alpha}2-Adrenoceptor Activation? Circ. Res., September 28, 2007; 101(7): 642 - 644. [Full Text] [PDF]
|
|