Neuron-Derived Semaphorin 3A Is an Early Inducer of Vascular Permeability in Diabetic Retinopathy via Neuropilin-1

被引：126

作者：

Cerani, Agustin ^{[1
,2
]}

Tetreault, Nicolas ^{[2
,3
]}

Menard, Catherine ^{[2
]}

Lapalme, Eric ^{[1
]}

Patel, Chintan ^{[1
]}

Sitaras, Nicholas ^{[1
]}

Beaudoin, Felix ^{[2
]}

Leboeuf, Dominique ^{[2
]}

De Guire, Vincent ^{[2
]}

Binet, Francois ^{[1
]}

Dejda, Agnieszka ^{[2
]}

Rezende, Flavio A. ^{[1
]}

Miloudi, Khalil ^{[3
]}

Sapieha, Przemyslaw ^{[1
,2
,3
]}

机构：

[1] Univ Montreal, Maisonneuve Rosemont Hosp Res Ctr, Dept Ophthalmol, Montreal, PQ H1T 2M4, Canada

[2] Univ Montreal, Maisonneuve Rosemont Hosp Res Ctr, Dept Biochem, Montreal, PQ H1T 2M4, Canada

[3] McGill Univ, Dept Neurol Neurosurg, Montreal, PQ H3A 2B4, Canada

来源：

CELL METABOLISM | 2013年 / 18卷 / 04期

基金：

加拿大健康研究院;

关键词：

ENDOTHELIAL GROWTH-FACTOR; RETINAL ANGIOGENESIS; TUMOR ANGIOGENESIS; VEGF; BINDING; CELLS; MICE; COMPLEXES; MODEL; MOUSE;

D O I：

10.1016/j.cmet.2013.09.003

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

The deterioration of the inner blood-retinal barrier and consequent macular edema is a cardinal manifestation of diabetic retinopathy (DR) and the clinical feature most closely associated with loss of sight. We provide evidence from both human and animal studies for the critical role of the classical neuronal guidance cue, semaphorin 3A, in instigating pathological vascular permeability in diabetic retinas via its cognate receptor neuropilin-1. We reveal that semaphorin 3A is induced in early hyperglycemic phases of diabetes within the neuronal retina and precipitates initial breakdown of endothelial barrier function. We demonstrate, by a series of orthogonal approaches, that neutralization of semaphorin 3A efficiently prevents diabetes-induced retinal vascular leakage in a stage of the disease when vascular endothelial growth factor neutralization is inefficient. These observations were corroborated in Tg(Cre-Esr1)/Nrp1(flox/flox) conditional knockout mice. Our findings identify a therapeutic target for macular edema and provide further evidence for neurovascular crosstalk in the pathogenesis of DR.

引用

页码：505 / 518

页数：14

共 70 条

[1] Semaphorin 3A suppresses VEGF-mediated angiogenesis yet acts as a vascular permeability factor [J].