title: Lysophosphatidic acid receptors 1 and 2 play roles in regulation of vascular injury responses but not blood pressure.
abstract: Phenotypic modulation of vascular smooth muscle cells (SMCs) is essential for the development of intimal hyperplasia. Lysophosphatidic acid (LPA) is a serum component that can promote phenotypic modulation of cultured SMCs, but an endogenous role for this bioactive lipid as a regulator of SMC function in vivo has not been established. Ligation injury of the carotid artery in mice increased levels in the vessel of both autotaxin, the lysophospholipase D enzyme responsible for generation of extracellular LPA, and 2 LPA responsive G protein-coupled receptors 1 (LPA1) and 2 (LPA2). LPA1(-/-)2(-/-) mice were partially protected from the development of injury-induced neointimal hyperplasia, whereas LPA1(-/-) mice developed larger neointimal lesions after injury. Growth in serum, LPA-induced extracellular signal-regulated protein kinase activation, and migration to LPA and serum were all attenuated in SMCs isolated from LPA1(-/-)2(-/-) mice. In contrast, LPA1(-/-) SMCs exhibited enhanced migration resulting from an upregulation of LPA3. However, despite their involvement in intimal hyperplasia, neither LPA1 nor LPA2 was required for dedifferentiation of SMCs following vascular injury or dedifferentiation of isolated SMCs in response to LPA or serum in vitro. Similarly, neither LPA1 nor LPA2 was required for LPA to elicit a transient increase in blood pressure following intravenous administration of LPA to mice. These results identify a role for LPA1 and LPA2 in regulating SMC migratory responses in the context of vascular injury but suggest that additional LPA receptor subtypes are required for other LPA-mediated effects in the vasculature.
authors.affiliation: Division of Cardiovascular Medicine, The Gill Heart Institute, Lexington, KY 40536, USA.
authors.forename: Manikandan
authors.initials: M
authors.lastname: Panchatcharam
authors.forename: Sumitra
authors.initials: S
authors.lastname: Miriyala
authors.forename: Fanmuyi
authors.initials: F
authors.lastname: Yang
authors.forename: Mauricio
authors.initials: M
authors.lastname: Rojas
authors.forename: Christopher
authors.initials: C
authors.lastname: End
authors.forename: Christopher
authors.initials: C
authors.lastname: Vallant
authors.forename: Anping
authors.initials: A
authors.lastname: Dong
authors.forename: Kevin
authors.initials: K
authors.lastname: Lynch
authors.forename: Jerold
authors.initials: J
authors.lastname: Chun
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Morris
authors.forename: Susan S
authors.initials: SS
authors.lastname: Smyth
mesh_terms: D000818:Animals; D001013:Aorta, Thoracic / Q000378:metabolism / Q000473:pathology / Q000502:physiology; D001794:Blood Pressure / Q000235:genetics; D002465:Cell Movement / Q000235:genetics; D008246:Lysophospholipids / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008822:Mice, Transgenic; D020033:Protein Isoforms / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D049368:Receptors, Lysophosphatidic Acid / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D014652:Vascular Diseases / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology*
chemical_list: D008246:Lysophospholipids; D020033:Protein Isoforms; D049368:Receptors, Lysophosphatidic Acid; C032881:lysophosphatidic acid