Semaphorin 3E–Plexin-D1 signaling regulates VEGF function in developmental angiogenesis via a feedback mechanism

Genes and Development - Tập 25 Số 13 - Trang 1399-1411 - 2011
Jiha Kim1, Won-Jong Oh2, Nicholas Gaiano3, Yutaka Yoshida4, Chenghua Gu2
1Department of Neurobiology, Harvard Medical School, Boston, Massachusetts 02115 USA
2Harvard University
3Johns Hopkins University
4Cincinnati Children's Hospital Medical Center

Tóm tắt

Blood vessel networks are typically formed by angiogenesis, a process in which new vessels form by sprouting of endothelial cells from pre-existing vessels. This process is initiated by vascular endothelial growth factor (VEGF)-mediated tip cell selection and subsequent angiogenic sprouting. Surprisingly, we found that VEGF directly controls the expression of Plexin-D1, the receptor for the traditional repulsive axon guidance cue, semaphorin 3E (Sema3E). Sema3E–Plexin-D1 signaling then negatively regulates the activity of the VEGF-induced Delta-like 4 (Dll4)–Notch signaling pathway, which controls the cell fate decision between tip and stalk cells. Using the mouse retina as a model system, we show that Plexin-D1 is selectively expressed in endothelial cells at the front of actively sprouting blood vessels and its expression is tightly controlled by VEGF secreted by surrounding tissues. Therefore, although the Sema3E secreted by retinal neurons is evenly distributed throughout the retina, Sema3E–Plexin-D1 signaling is spatially controlled by VEGF through its regulation of Plexin-D1. Moreover, we show that gain and loss of function of Sema3E and Plexin-D1 disrupts normal Dll4 expression, Notch activity, and tip/stalk cell distribution in the retinal vasculature. Finally, the retinal vasculature of mice lacking sema3E or plexin-D1 has an uneven growing front, a less-branched vascular network, and abnormal distribution of dll4-positive cells. Lowering Notch activity in the mutant mice can reverse this defect, solidifying the observation that Dll4–Notch signaling is regulated by Sema3E–Plexin-D1 and is required for its function in vivo. Together, these data reveal a novel role of Sema3E–Plexin-D1 function in modulating angiogenesis via a VEGF-induced feedback mechanism.

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Tài liệu tham khảo

10.1101/cshperspect.a001875

10.1016/j.cell.2009.03.025

10.1038/nature03875

10.1172/JCI42118

10.1073/pnas.93.2.589

10.1016/j.neuron.2007.10.019

10.1016/0026-2862(88)90028-3

10.1182/blood-2010-02-270819

10.1161/ATVBAHA.109.185165

2002, Retinal vascular development is mediated by endothelial filopodia, a preexisting astrocytic template and specific R-cadherin adhesion, Invest Ophthalmol Vis Sci, 43, 3500

10.1038/ni1164

10.1016/j.ceb.2010.08.010

10.1007/s10456-007-9065-1

10.1016/j.tcb.2009.01.001

10.4161/org.4.4.7414

10.1083/jcb.200302047

10.1016/j.devcel.2004.06.002

10.1074/jbc.M201681200

10.1126/science.1105416

10.1006/dbio.2002.0597

10.1038/nature05571

10.1038/ncb2103

10.1242/dev.003244

10.1073/pnas.0611206104

10.1016/j.devcel.2009.01.015

10.1006/exer.1997.0365

10.1038/386671a0

10.1101/gad.1589207

10.1101/gad.242002

1996, Roles of vascular endothelial growth factor and astrocyte degeneration in the genesis of retinopathy of prematurity, Invest Ophthalmol Vis Sci, 37, 290

10.1182/blood-2009-07-230284

10.1073/pnas.0611177104

10.1038/sj.bjc.6604484

10.1016/j.devcel.2004.06.008

10.1016/j.yexcr.2005.10.030

2010, Astrocyte hypoxic response is essential for pathological but not developmental angiogenesis of the retina, Glia, 58, 1177, 10.1002/glia.20997

10.1016/j.ydbio.2008.09.031

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Genes and Development

Tập 25 Số 13

1399-1411

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