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 (SMC) is essential for the development of intimal hyperplasia. Lysophosphatidic acid (LPA) is a serum component that can promote phenotypic modulation of cultured SMC, 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 lysophospholipaseD enzyme responsible for generation of extracellular LPA, and two 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 ERK activation, and migration to LPA and serum were all attenuated in SMC 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 were required for dedifferentiation of SMC following vascular injury or dedifferentiation of isolated SMC in response to LPA or serum in vitro. Similarly, neither LPA1 nor LPA2 were required for LPA to elicit a transient increase in blood pressure following intravenous administration of LPA to mice. These results identify a role for LPA and two defined LPA receptors 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.

LPA receptor signaling: pharmacology, physiology, and pathophysiology

“…Also, LPA 2 activation can inhibit EGF-induced migration and invasion of pancreatic cancer cells through the G 12/13 /Rho pathway (144). These data lend support to the pattern of transactivation and cross-regulation between GPCRs and receptor tyrosine kinases in a variety of settings (145) (95,149). Exogenous LPA exposure in ex vivo cerebral cortical cultures decreased cell death, increased NPC cell cycle exit, and produced early terminal mitosis.…”

“…Ki16425 also inhibited neointima formation and SMC recruitment to the injury site after wire-induced carotid injury (151). Neither LPA 1 nor LPA 2 was required for dedifferentiation of SMCs following vascular injury in vivo or LPA exposure ex vivo, nor were they required for LPA-induced blood pressure increases (149). These observations indicate the likely involvement of other LPA receptor subtypes in these processes.…”

“…Specifi cally, LPA 1 and LPA 2 were found to exhibit opposite effects on primary vascular smooth muscle cells and injuryinduced neointimal hyperplasia (149). Vascular smooth muscle cell (SMC) migration was increased in Lpar1 Ϫ/Ϫ mice but was partially attenuated in Lpar1…”

LPAR2 (lysophosphatidic acid receptor 2)

“…The PTPL1 phosphatase dephosphorylates TRIP6 and attenuates LPA-induced cell migration, thus acting as a negative regulator of cell motility . LPA2 has also been identified to be involved in regulating smooth muscle cell migration in the context of vascular injury (Panchatcharam et al, 2008). Recently, two groups have implicated LPA2 signaling in TGF-β activation in mouse models of lung fibrosis and ischemia-reperfusion injury.…”

Lysophosphatidic Acid Inhibits CC Chemokine Ligand 5/RANTES Production by Blocking IRF-1–Mediated Gene Transcription in Human Bronchial Epithelial Cells

“…LPA stimulates the secretion of IL-8 from airway epithelium, inducing the infiltration of neutrophils (15). Furthermore, LPA has been reported to be involved in the production of angiogenic factors (16), pulmonary vascular injury (17), and the development of allergic airway inflammation (18). These findings suggest that LPA might accelerate inflammation in respiratory diseases such as acute lung injury/acute respiratory distress syndrome, pulmonary fibrosis, and asthma.…”