Role of Src in Vascular Hyperpermeability Induced by Advanced Glycation End Products

Overview

Journal Sci Rep

Specialty Science

Date 2015 Sep 19

PMID 26381822

Citations 27

Authors

Weijin Zhang

Qiulin Xu

Jie Wu

Xiaoyan Zhou

Jie Weng

Jing Xu

Weiju Wang

Qiaobing Huang

Xiaohua Guo

Affiliations

Soon will be listed here.

Abstract

The disruption of microvascular barrier in response to advanced glycation end products (AGEs) stimulation contributes to vasculopathy associated with diabetes mellitus. Here, to study the role of Src and its association with moesin, VE-cadherin and focal adhesion kinase (FAK) in AGE-induced vascular hyperpermeability, we verified that AGE induced phosphorylation of Src, causing increased permeability in HUVECs. Cells over-expressed Src displayed a higher permeability after AGE treatment, accompanied with more obvious F-actin rearrangement. Activation of Src with pcDNA3/flag-Src(Y530F) alone duplicated these effects. Inhibition of Src with siRNA, PP2 or pcDNA3/flag-Src(K298M) abolished these effects. The pulmonary microvascular endothelial cells (PMVECs) isolated from receptor for AGEs (RAGE)-knockout mice decreased the phosphorylation of Src and attenuated the barrier dysfunction after AGE-treatment. In vivo study showed that the exudation of dextran from mesenteric venules was increased in AGE-treated mouse. This was attenuated in RAGE knockout or PP2-pretreated mice. Up-regulation of Src activity induced the phosphorylation of moesin, as well as activation and dissociation of VE-cadherin, while down-regulation of Src abolished these effects. FAK was also proved to interact with Src in HUVECs stimulated with AGEs. Our studies demonstrated that Src plays a critical role in AGE-induced microvascular hyperpermeability by phosphorylating moesin, VE-cadherin, and FAK respectively.

Citing Articles

Isaridin E Protects against Sepsis by Inhibiting Von Willebrand Factor-Induced Endothelial Hyperpermeability and Platelet-Endothelium Interaction.

Liu Y, Chen W, Zeng Y, Li Z, Zheng H, Pan N Mar Drugs. 2024; 22(6).

PMID: 38921594 PMC: 11204489. DOI: 10.3390/md22060283.

Endothelial β-catenin upregulation and Y142 phosphorylation drive diabetic angiogenesis via upregulating KDR/HDAC9.

Chen Z, Lin B, Yao X, Weng J, Liu J, He Q Cell Commun Signal. 2024; 22(1):182.

PMID: 38491522 PMC: 10941375. DOI: 10.1186/s12964-024-01566-1.

5α-Hydroxycostic acid inhibits choroidal neovascularization in rats through a dual signalling pathway mediated by VEGF and angiopoietin 2.

Lei W, Xu H, Yao H, Li L, Wang M, Zhou X Mol Med. 2023; 29(1):151.

PMID: 37914992 PMC: 10621151. DOI: 10.1186/s10020-023-00674-x.

Edema and lymphatic clearance: molecular mechanisms and ongoing challenges.

Breslin J Clin Sci (Lond). 2023; 137(18):1451-1476.

PMID: 37732545 PMC: 11025659. DOI: 10.1042/CS20220314.

Corneal Edema in Inducible Knockout Is Initiated by Mitochondrial Superoxide Induced Src Kinase Activation.

Ogando D, Kim E, Li S, Bonanno J Cells. 2023; 12(11).

PMID: 37296649 PMC: 10253072. DOI: 10.3390/cells12111528.

References

Niiya Y, Abumiya T, Yamagishi S, Takino J, Takeuchi M . Advanced glycation end products increase permeability of brain microvascular endothelial cells through reactive oxygen species-induced vascular endothelial growth factor expression. J Stroke Cerebrovasc Dis. 2011; 21(4):293-8. DOI: 10.1016/j.jstrokecerebrovasdis.2010.09.002. View

Koss M, Pfeiffer 2nd G, Wang Y, Thomas S, Yerukhimovich M, Gaarde W . Ezrin/radixin/moesin proteins are phosphorylated by TNF-alpha and modulate permeability increases in human pulmonary microvascular endothelial cells. J Immunol. 2006; 176(2):1218-27. DOI: 10.4049/jimmunol.176.2.1218. View

Lehr H, Bittinger F, Kirkpatrick C . Microcirculatory dysfunction in sepsis: a pathogenetic basis for therapy?. J Pathol. 2000; 190(3):373-86. DOI: 10.1002/(SICI)1096-9896(200002)190:3<373::AID-PATH593>3.0.CO;2-3. View

Hou F, Miyata T, Boyce J, Yuan Q, Chertow G, Kay J . beta(2)-Microglobulin modified with advanced glycation end products delays monocyte apoptosis. Kidney Int. 2001; 59(3):990-1002. DOI: 10.1046/j.1523-1755.2001.059003990.x. View

Mehta D, Tiruppathi C, Sandoval R, Minshall R, Holinstat M, Malik A . Modulatory role of focal adhesion kinase in regulating human pulmonary arterial endothelial barrier function. J Physiol. 2002; 539(Pt 3):779-89. PMC: 2290187. DOI: 10.1113/jphysiol.2001.013289. View

Eliceiri B, Puente X, Hood J, Stupack D, Schlaepfer D, Huang X . Src-mediated coupling of focal adhesion kinase to integrin alpha(v)beta5 in vascular endothelial growth factor signaling. J Cell Biol. 2002; 157(1):149-60. PMC: 2173263. DOI: 10.1083/jcb.200109079. View

Brizzi M, Dentelli P, Gambino R, Cabodi S, Cassader M, Castelli A . STAT5 activation induced by diabetic LDL depends on LDL glycation and occurs via src kinase activity. Diabetes. 2002; 51(11):3311-7. DOI: 10.2337/diabetes.51.11.3311. View

Tinsley J, Ustinova E, Xu W, Yuan S . Src-dependent, neutrophil-mediated vascular hyperpermeability and beta-catenin modification. Am J Physiol Cell Physiol. 2002; 283(6):C1745-51. DOI: 10.1152/ajpcell.00230.2002. View

Nathan C . Points of control in inflammation. Nature. 2002; 420(6917):846-52. DOI: 10.1038/nature01320. View

10.

Luo P, Peng H, Li C, Ye Z, Tang H, Tang Y . Advanced glycation end products induce glomerular endothelial cell hyperpermeability by upregulating matrix metalloproteinase activity. Mol Med Rep. 2015; 11(6):4447-53. DOI: 10.3892/mmr.2015.3269. View

11.

Campbell E, McDuff E, Tatarov O, Tovey S, Brunton V, Cooke T . Phosphorylated c-Src in the nucleus is associated with improved patient outcome in ER-positive breast cancer. Br J Cancer. 2008; 99(11):1769-74. PMC: 2600702. DOI: 10.1038/sj.bjc.6604768. View

12.

Laird A, Li G, Moss K, Blake R, Broome M, Cherrington J . Src family kinase activity is required for signal tranducer and activator of transcription 3 and focal adhesion kinase phosphorylation and vascular endothelial growth factor signaling in vivo and for anchorage-dependent and -independent growth of.... Mol Cancer Ther. 2003; 2(5):461-9. View

13.

Bolton W, Cattran D, Williams M, Adler S, Appel G, Cartwright K . Randomized trial of an inhibitor of formation of advanced glycation end products in diabetic nephropathy. Am J Nephrol. 2003; 24(1):32-40. DOI: 10.1159/000075627. View

14.

Basta G, Schmidt A, De Caterina R . Advanced glycation end products and vascular inflammation: implications for accelerated atherosclerosis in diabetes. Cardiovasc Res. 2004; 63(4):582-92. DOI: 10.1016/j.cardiores.2004.05.001. View

15.

Vlassara H . Receptor-mediated interactions of advanced glycosylation end products with cellular components within diabetic tissues. Diabetes. 1992; 41 Suppl 2:52-6. DOI: 10.2337/diab.41.2.s52. View

16.

Berryman M, Franck Z, BRETSCHER A . Ezrin is concentrated in the apical microvilli of a wide variety of epithelial cells whereas moesin is found primarily in endothelial cells. J Cell Sci. 1993; 105 ( Pt 4):1025-43. DOI: 10.1242/jcs.105.4.1025. View

17.

Reddy M, Li S, Sahar S, Kim Y, Xu Z, Lanting L . Key role of Src kinase in S100B-induced activation of the receptor for advanced glycation end products in vascular smooth muscle cells. J Biol Chem. 2006; 281(19):13685-13693. DOI: 10.1074/jbc.M511425200. View

18.

Yamagishi S, Nakamura K, Matsui T, Inagaki Y, Takenaka K, Jinnouchi Y . Pigment epithelium-derived factor inhibits advanced glycation end product-induced retinal vascular hyperpermeability by blocking reactive oxygen species-mediated vascular endothelial growth factor expression. J Biol Chem. 2006; 281(29):20213-20. DOI: 10.1074/jbc.M602110200. View

19.

Goldin A, Beckman J, Schmidt A, Creager M . Advanced glycation end products: sparking the development of diabetic vascular injury. Circulation. 2006; 114(6):597-605. DOI: 10.1161/CIRCULATIONAHA.106.621854. View

20.

Gavard J, Gutkind J . VEGF controls endothelial-cell permeability by promoting the beta-arrestin-dependent endocytosis of VE-cadherin. Nat Cell Biol. 2006; 8(11):1223-34. DOI: 10.1038/ncb1486. View