p2y5/LPA(6) attenuates LPA(1)-mediated VE-cadherin translocation and cell-cell dissociation through G(12/13) protein-Src-Rap1.
Cardiovasc Res
; 92(1): 149-58, 2011 Oct 01.
Article
in En
| MEDLINE
| ID: mdl-21632882
ABSTRACT
AIMS:
We investigated the mechanisms of action of lysophosphatidic acid (LPA) to regulate vascular endothelial (VE)-cadherin dynamics and cell-cell contact. METHODS ANDRESULTS:
While a low concentration of LPA stimulated VE-cadherin internalization and subsequent cell-cell dissociation, a high concentration of LPA masked the disruptive actions on VE-cadherin and protected the barrier function in human vascular endothelial cells. Knockdown experiments of major LPA receptor subtypes, i.e. LPA(1) and p2y5 (also termed LPA(6)), with their specific small interfering RNAs, showed that LPA(1) and LPA(6) mediate the LPA-induced disruptive and protective actions on barrier integrity, respectively. LPA(6)-mediated tube formation, reflecting stabilization of barrier integrity, was confirmed by in vitro angiogenesis assay. The LPA(1)-mediated disruptive actions were inhibited by pertussis toxin, dominant-negative Rac1, and inhibitors for c-Jun NH(2)-terminal kinase (JNK) and p38 mitogen-activated protein kinase (p38MAPK), but not by dominant-negative RhoA. In contrast, the LPA(6)-mediated protective actions were associated with activation of Src and Rap1 and attenuated by abrogation of their activities. Further characterization showed that Rap1 is located downstream of Src and dependent on C3G, a Rap1 guanine nucleotide exchange factor. Finally, an LPA antagonist significantly inhibited lactic acid-induced limb lesions in vivo, which may be attributed to dysfunction of endothelial cells.CONCLUSION:
LPA induced disruption and protection of VE-cadherin integrity through LPA(1)-G(i) protein-Rac1-JNK/p38MAPK and LPA(6)-G(12/13) protein-Src-C3G-Rap1 pathways, respectively.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Antigens, CD
/
Cadherins
/
Receptors, Purinergic P2
/
Src-Family Kinases
/
GTPase-Activating Proteins
/
GTP-Binding Protein alpha Subunits, G12-G13
/
Receptors, Lysophosphatidic Acid
Limits:
Animals
/
Humans
/
Male
Language:
En
Journal:
Cardiovasc Res
Year:
2011
Document type:
Article
Affiliation country:
Japón
Publication country:
ENGLAND
/
ESCOCIA
/
GB
/
GREAT BRITAIN
/
INGLATERRA
/
REINO UNIDO
/
SCOTLAND
/
UK
/
UNITED KINGDOM