Sphingosine-1-Phosphate and Lysophosphatidic Acid Stimulate Endothelial Cell Migration

Lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P) are potent lipid growth factors with similar abilities to stimulate cytoskeleton-based cellular functions. Their effects are mediated by a subfamily of G protein-coupled receptors (GPCRs) encoded by endothelial differentiation genes ( edgs). We hypothesize that large quantities of LPA and S1P generated by activated platelets may influence endothelial cell functions. Using an in vitro wound healing assay, we observed that LPA and S1P stimulated closure of wounded monolayers of human umbilical vein endothelial cells and adult bovine aortic endothelial cells, which express LPA receptor Edg2, and S1P receptors Edg1 and Edg3. The two major components of wound healing, cell migration and proliferation, were stimulated individually by both lipids. LPA and S1P also stimulated intracellular Ca2+mobilization and mitogen-activated protein kinase (MAPK) phosphorylation. Pertussis toxin partially blocked the effects of both lipids on endothelial cell migration, MAPK phosphorylation, and Ca2+ mobilization, implicating Gi/o-coupled Edg receptor signaling in endothelial cells. LPA and S1P did not cross-desensitize each other in Ca2+ responses, suggesting involvement of distinct receptors. Thus LPA and S1P affect endothelial cell functions through signaling pathways activated by distinct GPCRs and may contribute to the healing of wounded vasculatures.

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Endothelial Cell Migration on RGD-Peptide-Containing PEG Hydrogels in the Presence of Sphingosine 1-Phosphate

Biophysical Journal ◽

10.1529/biophysj.107.109074 ◽

2008 ◽

Vol 94 (1) ◽

pp. 273-285 ◽

Cited By ~ 40

Author(s):

Bradley K. Wacker ◽

Shannon K. Alford ◽

Evan A. Scott ◽

Meghna Das Thakur ◽

Gregory D. Longmore ◽

...

Keyword(s):

Cell Migration ◽

Endothelial Cell ◽

Rgd Peptide ◽

Endothelial Cell Migration ◽

Peg Hydrogels ◽

Sphingosine 1 Phosphate

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High-Density Lipoprotein Stimulates Endothelial Cell Migration and Survival Through Sphingosine 1-Phosphate and Its Receptors

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/01.atv.0000079011.67194.5a ◽

2003 ◽

Vol 23 (7) ◽

pp. 1283-1288 ◽

Cited By ~ 170

Author(s):

Takao Kimura ◽

Koichi Sato ◽

Enkhzol Malchinkhuu ◽

Hideaki Tomura ◽

Kenichi Tamama ◽

...

Keyword(s):

Cell Migration ◽

Endothelial Cell ◽

High Density Lipoprotein ◽

Density Lipoprotein ◽

High Density ◽

Endothelial Cell Migration ◽

Sphingosine 1 Phosphate

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Autotaxin Signaling via Lysophosphatidic Acid Receptors Contributes to Vascular Endothelial Growth Factor–Induced Endothelial Cell Migration

Molecular Cancer Research ◽

10.1158/1541-7786.mcr-09-0288 ◽

2010 ◽

Vol 8 (3) ◽

pp. 309-321 ◽

Cited By ~ 47

Author(s):

Malgorzata M. Ptaszynska ◽

Michael L. Pendrak ◽

Mary L. Stracke ◽

David D. Roberts

Keyword(s):

Vascular Endothelial Growth Factor ◽

Cell Migration ◽

Endothelial Cell ◽

Growth Factor ◽

Lysophosphatidic Acid ◽

Endothelial Cell Migration ◽

Vascular Endothelial ◽

Endothelial Growth Factor ◽

Lysophosphatidic Acid Receptors

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Sphingosine 1-Phosphate-induced Endothelial Cell Migration Requires the Expression of EDG-1 and EDG-3 Receptors and Rho-dependent Activation of αvβ3- and β1-containing Integrins

Journal of Biological Chemistry ◽

10.1074/jbc.m009422200 ◽

2001 ◽

Vol 276 (15) ◽

pp. 11830-11837 ◽

Cited By ~ 210

Author(s):

Ji H. Paik ◽

Sung-suk Chae ◽

Menq-Jer Lee ◽

Shobha Thangada ◽

Timothy Hla

Keyword(s):

Cell Migration ◽

Endothelial Cell ◽

Molecular Mechanisms ◽

Cell Attachment ◽

Endothelial Cell Migration ◽

Endothelial Differentiation ◽

Focal Contact ◽

Sphingosine 1 Phosphate ◽

And Migration ◽

Differentiation Gene

Sphingosine 1-phosphate (SPP), a platelet-derived bioactive lysophospholipid, is a regulator of angiogenesis. However, molecular mechanisms involved in SPP-induced angiogenic responses are not fully defined. Here we report the molecular mechanisms involved in SPP-induced human umbilical vein endothelial cell (HUVEC) adhesion and migration. SPP-induced HUVEC migration is potently inhibited by antisense phosphothioate oligonucleotides against EDG-1 as well as EDG-3 receptors. In addition, C3 exotoxin blocked SPP-induced cell attachment, spreading and migration on fibronectin-, vitronectin- and Matrigel-coated surfaces, suggesting that endothelial differentiation gene receptor signaling via the Rho pathway is critical for SPP-induced cell migration. Indeed, SPP induced Rho activation in an adherence-independent manner, whereas Rac activation was dispensible for cell attachment and focal contact formation. Interestingly, both EDG-1 and -3 receptors were required for Rho activation. Since integrins are critical for cell adhesion, migration, and angiogenesis, we examined the effects of blocking antibodies against αvβ3, β1, or β3integrins. SPP induced Rho-dependent integrin clustering into focal contact sites, which was essential for cell adhesion, spreading and migration. Blockage of αvβ3- or β1-containing integrins inhibited SPP-induced HUVEC migration. Together our results suggest that endothelial differentiation gene receptor-mediated Rho signaling is required for the activation of integrin αvβ3as well as β1-containing integrins, leading to the formation of initial focal contacts and endothelial cell migration.

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Hic-5 promotes endothelial cell migration to lysophosphatidic acid

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00728.2006 ◽

2007 ◽

Vol 293 (1) ◽

pp. H193-H203 ◽

Cited By ~ 23

Author(s):

C. Avraamides ◽

M. E. Bromberg ◽

J. P. Gaughan ◽

S. M. Thomas ◽

A. Y. Tsygankov ◽

...

Keyword(s):

Cell Migration ◽

Endothelial Cell ◽

Focal Adhesion ◽

Lysophosphatidic Acid ◽

Fluorescent Protein ◽

Focal Adhesions ◽

Endothelial Cell Migration ◽

Erk Phosphorylation ◽

Green Fluorescent

Endothelial cell migration is critical for proper blood vessel development. Signals from growth factors and matrix proteins are integrated through focal adhesion proteins to alter cell migration. Hydrogen peroxide-inducible clone 5 (Hic-5), a paxillin family member, is enriched in the focal adhesions in bovine pulmonary artery endothelial (BPAE) cells, which migrate to lysophosphatidic acid (LPA) on denatured collagen. In this study, we investigate the role of Hic-5 in LPA-stimulated endothelial cell migration. LPA recruits Hic-5 to the focal adhesions and to the pseudopodia in BPAE cells plated on collagen, suggesting that recruitment of Hic-5 to focal adhesions is associated with endothelial cell migration. Knockdown of endogenous Hic-5 significantly decreases migration toward LPA, confirming involvement of Hic-5 in migration. To address the role of Hic-5 in endothelial cell migration, we exogenously expressed wild-type (WT) Hic-5 and green fluorescent protein Hic-5 C369A/C372A (LIM3 mutant) constructs in BPAE cells. WT Hic-5 expression increases chemotaxis of BPAE cells to LPA, whereas migration toward LPA of the green fluorescent protein Hic-5 C369A/C372A-expressing cells is similar to that shown in vector control cells. Additionally, ERK phosphorylation is enhanced in the presence of LPA in WT Hic-5 cells. A pharmacological inhibitor of MEK activity inhibits LPA-stimulated WT Hic-5 cell migration and ERK phosphorylation, suggesting Hic-5 enhances migration via MEK activation of ERK. Together, these studies indicate that Hic-5, a focal adhesion protein in endothelial cells, is recruited to the pseudopodia in the presence of LPA and enhances migration.

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