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Circulation Research. 2007;101:642-644
doi: 10.1161/CIRCRESAHA.107.161855
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(Circulation Research. 2007;101:642.)
© 2007 American Heart Association, Inc.

Editorials

Sympathetic Control of VEGF Angiogenic Signaling

Dual Regulations by {alpha}2-Adrenoceptor Activation?

Yuichi Hattori, Seiji Yamamoto, Naoyuki Matsuda

From the Department of Molecular and Medical Pharmacology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Japan.

Correspondence to Yuichi Hattori, Department of Molecular and Medical Pharmacology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan. E-mail yhattori{at}med.u-toyama.ac.jp



See related article, pages 682–691


Key Words: adrenergic receptors • angiogenesis • vascular endothelial growth factor • vascular endothelial growth factor receptors

It is now accepted that vascular endothelial growth factor (VEGF), a dimeric 46-kDa heparin-binding glycoprotein, is one of the most important vasculogenic and angiogenic factors reported to date. VEGF acts as a potent and specific mitogen for vascular endothelial cells in vitro and possesses a signal sequence which allows it to be secreted.1 Furthermore, numerous studies in vivo have shown that expression of VEGF and its receptors is upregulated during angiogenesis under physiological and pathological processes, such as development of the embryo,2–4 estrous cycle,5 tumor growth,6,7 and wound healing.8 Thus, VEGF plays an important role in the formation of new vessels from existing ones and the microvascular remodeling which involves structural alterations—usually enlargement—of arterioles, capillaries, or venules, in inflammatory or neoplastic diseases.

Different mechanisms appear to participate in the regulation of VEGF mRNA expression. It is well known that low oxygen tension is a strong inducer of VEGF mRNA expression in a variety of cells.6,9 Besides hypoxia-sensitive elements, the VEGF promoter region contains potential binding sites for the transcription factors AP-1, AP-2, and SP-1.10 Consistent with this fact, cAMP analogues and phorbol esters have been shown to upregulate VEGF mRNA in rat aortic smooth muscle cells,11 NIH 3T3 cells,12 or ovarian bovine granulosa cells,13 suggesting that VEGF expression is controlled by protein kinase A (PKA)- and protein kinase C (PKC)-mediated signals. Very interestingly, norepinephrine has been demonstrated to increase VEGF expression in murine brown adipocytes.14–16 Stimulation of ß-adrenoceptors with norepinephrine activates adenylate cyclase via Gs regulatory proteins, resulting in an increased production of the second messenger cAMP, which leads to activation of PKA. Indeed, norepinephrine-induced upregulation of VEGF expression has been proven to be exclusively dependent on a ß-adrenoceptor–mediated increase in cAMP levels and PKA activity.16 In addition, this pathway may use a Src-dependent pathway that branches off from the Src-Erk1/2 signaling cascade (Figure).16 Although the norepinephrine effect on VEGF expression in brown adipocytes could be mimicked by the ß3-adrenoceptor agonists BRL-37344 and CGP-12177,16 a recent report has demonstrated that the ß2-adrenoceptor agonists zilpaterol and clenbuterol induce the release of VEGF by macrophages exposed to endotoxin in a concentration-dependent manner,17 and the other study has suggested that both ß1- and ß2-adrenoceptors may be involved in norepinephrine-induced VEGF production in ovarian cancer cell lines.18 These findings imply that all subtypes of ß-adrenoceptors would mediate the increasing effect of norepinephrine on VEGF expression depending on cell types. However, it should be kept in mind that ß-adrenergic stimulation of VEGF expression may not necessarily be of major significance in regulating physiological angiogenesis. On the other hand, involvement of {alpha}1-adrenoceptors and the signaling pathway PKC activation in norepinephrine-induced VEGF expression in brown adipocytes appears to be minimal,16 and, conversely, it has been reported that the {alpha}1-adrenoceptor antagonist prazosin triggers the augmented production of VEGF in mouse skeletal muscles through shear stress–dependent endothelial nitric oxide synthase activation.19


Figure 1
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  		Figure. Schematic depicts adrenergic signals for angiogenesis involving the VEGF system. See text for details. NE indicates norepinephrine; AC, adenylate cyclase; KDR, VEGF receptor-2.

In this issue of Circulation Research, Muthig et al demonstrate a critical role for {alpha}2B-adrenoceptors in VEGF-associated angiogenic regulation in the placenta via the suppression of expression of the VEGF receptor-1 (Flt-1) and its soluble splice variant (sFlt-1).20 The authors created mice with a targeted deletion in the gene encoding {alpha}2B-adrenoceptors which were lost during the embryonic period because of a defect in placenta vascular labyrinth formation. They found that deletion of the {alpha}2B-adrenoceptor gene resulted in upregulation of sFlt-1 in spongiotrophoblast cells with a vasculogenesis defect in the placenta labyrinth and that neutralization of sFlt-1 by a specific antibody completely prevented the vascular defect in {alpha}2B-deficient placentae during mouse embryonic development.

Mammalian placentation requires extensive angiogenesis to establish a suitable vascular network for the supply of oxygen and nutrients to the fetus. In tissues where blood vessel growth is occurring, the net angiogenic effect is controlled by the balance between angiogenic inducers and inhibitors. The angiogenic inhibitor sFlt-1 is highly expressed by normal cytotrophoblasts21 and further elevated in cytotrophoblasts from preeclamptic placentae.22 Thus, elevated expression of sFlt-1 in preeclampsia plays a major role in the pathogenesis of this serious disorder of human pregnancy. Although the mechanisms regulating the synthesis and secretion of sFlt-1 during pregnancy are largely unknown, quite recent studies have indicated that thrombin and angiotensin II may act as an enhancer of sFlt-1 expression during pregnancy.23,24 Furthermore, despite the fact that hypoxic conditions enhance expression of VEGF,6,9 increased sFlt-1 expression in the human placenta under low oxygen condition mediated by hypoxia inducible factor-1{alpha} has been demonstrated.25 The study by Muthig et al not only suggests a novel mechanism of regulation of angiogenesis by alternative splicing of sFlt-1 mRNA but has important implications for understanding the pathogenesis of preeclampsia.

{alpha}2-Adrenoceptors are essential presynaptic regulators of norepinephrine release from sympathetic nerves. Thus, presynaptic {alpha}2-adrenoceptors are linked to inhibition of norepinephrine release from the sympathetic nerve terminals.26 This would result in a reduction in norepinephrine-induced upregulation of VEGF expression via ß-adrenoceptor activation. From the study by Muthig et al, conversely, {alpha}2-adrenoceptors may potentially lead to activation of VEGF-mediated angiogenesis by repressing sFlt-1 expression. Therefore, {alpha}2-adrenoceptors may modulate VEGF function and thus angiogenesis because of the opposite dual regulations (Figure). However, whether suppression of antiangiogenic sFlt-1 expression by {alpha}2B-adrenoceptors can operate in angiogenesis and vasculogenesis in the adult organism remains the subject of ongoing studies.


*    Acknowledgments
 
Sources of Funding

This work was supported by a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science of Technology of Japan.

Disclosures

None.


*    Footnotes
 
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.


*    References
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 *References
 

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Related Article:

Upregulation of Soluble Vascular Endothelial Growth Factor Receptor 1 Contributes to Angiogenesis Defects in the Placenta of {alpha}2B-Adrenoceptor–Deficient Mice
Verena Muthig, Ralf Gilsbach, Miriam Haubold, Melanie Philipp, Tomi Ivacevic, Manfred Gessler, and Lutz Hein
Circ. Res. 2007 101: 682-691. [Abstract] [Full Text] [PDF]




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