RCAN1.4 regulates VEGFR-2 internalisation, cell polarity and migration in human microvascular endothelial cells

被引：78

作者：

Alghanem, Ahmad F. ^{[1
,5
]}

Wilkinson, Emma L. ^{[1
]}

Emmett, Maxine S. ^{[1
]}

Aljasir, Mohammad A. ^{[1
]}

Holmes, Katherine ^{[1
]}

Rothermel, Beverley A. ^{[2
,3
]}

Simms, Victoria A. ^{[4
]}

Heath, Victoria L. ^{[4
]}

Cross, Michael J. ^{[1
]}

机构：

[1] Univ Liverpool, Inst Translat Med, Dept Mol & Clin Pharmacol, MRC Ctr Drug Safety Sci, Liverpool L69 3GE, Merseyside, England

[2] Univ Texas Southwestern Med Ctr Dallas, Dept Internal Med, Dallas, TX 75390 USA

[3] Univ Texas Southwestern Med Ctr Dallas, Dept Mol Biol, Dallas, TX 75390 USA

[4] Univ Birmingham, Inst Cardiovasc Sci, Med Sch, Birmingham B15 2TT, W Midlands, England

[5] King Saud bin Abdulaziz Univ Hlth Sci, KAIMRC Eastern Reg, Al Hasa 31982, Saudi Arabia

来源：

ANGIOGENESIS | 2017年 / 20卷 / 03期

关键词：

VEGFR-2; RCAN1; Endothelial; Polarisation; Migration; Angiogenesis; DOWN-SYNDROME; GROWTH-FACTOR; DSCR1; ADAPT78; RECEPTOR; CALCINEURIN; ANGIOGENESIS; GENE; ENDOCYTOSIS; ACTIVATION; MECHANISMS;

D O I：

10.1007/s10456-017-9542-0

中图分类号：

R6 [外科学];

学科分类号：

100210 [外科学];

摘要：

Regulator of calcineurin 1 (RCAN1) is an endogenous inhibitor of the calcineurin pathway in cells. It is expressed as two isoforms in vertebrates: RCAN1.1 is constitutively expressed in most tissues, whereas transcription of RCAN1.4 is induced by several stimuli that activate the calcineurin-NFAT pathway. RCAN1.4 is highly upregulated in response to VEGF in human endothelial cells in contrast to RCAN1.1 and is essential for efficient endothelial cell migration and tubular morphogenesis. Here, we show that RCAN1.4 has a role in the regulation of agonist-stimulated VEGFR-2 internalisation and establishment of endothelial cell polarity. siRNA-mediated gene silencing revealed that RCAN1 plays a vital role in regulating VEGF-mediated cytoskeletal reorganisation and directed cell migration and sprouting angiogenesis. Adenoviral-mediated overexpression of RCAN1.4 resulted in increased endothelial cell migration. Antisense-mediated morpholino silencing of the zebrafish RCAN1.4 orthologue revealed a disrupted vascular development further confirming a role for the RCAN1.4 isoform in regulating vascular endothelial cell physiology. Our data suggest that RCAN1.4 plays a novel role in regulating endothelial cell migration by establishing endothelial cell polarity in response to VEGF.

引用

页码：341 / 358

页数：18

共 54 条

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INTRACELLULAR POOLS OF TRANSFERRIN RECEPTORS RESULT FROM CONSTITUTIVE INTERNALIZATION OF UNOCCUPIED RECEPTORS [J].