Lysophospholipid mediators in the vasculature

Abstract

Acting through cell surface receptors, “extracellular” lysophosphatidic acid (LPA) influences cell growth, differentiation, apoptosis and development in a wide spectrum of settings [1–5]. Within the vasculature, smooth muscle cells [6, 7], endothelial cells [8] and platelets [9, 10] display notable responses to LPA [11, 12], which likely regulate blood vessel development and contribute to vascular pathology. The bioactive effects of LPA are mediated by a family of G-protein coupled receptors with at least six members (termed LPA1-6 that are encoded by the LPAR genes in humans and Lpar in mice) [1–3]. LPA may also serve as a ligand for the receptor for advanced glycation end products (RAGE) [13]. This review summarizes evidence to support a role for LPA signaling in vascular biology based on studies of LPA receptors and enzymes that produce or metabolize the lipid (Figure 1). Figure 1 Autotaxin (ATX) and LPA actions in blood and vascular cells. LPA receptors The receptors for LPA are widely distributed on blood and vascular cells. In preclinical animal models, targeting the LPA receptors genetically and pharmacologically suggests that they may contribute to vascular injury and inflammatory responses, as well as endothelial barrier function and vascular stability. Single and multiple deletions of LPA receptors in mice produce differing vascular phenotypes. Deficiency of Lpar1, which results in 50% neonatal lethality, gives rise to the development of spontaneous frontal hematomas [14]. This suggests a role for LPA1 in stabilization of vessels, as no defect in hemostasis has been observed in these animals. In experimental arterial injury models, LPA1 regulates the development of intimal hyperplasia, a complex response involving inflammation and smooth muscle cell proliferation and migration. LPA1 may influence the vascular remodeling response via the Gα12/Gα13 pathway that couples to RhoGEF to activate RhoA, given the similarities in development on intimal hyperplasia after injury in the Lpar1−/− mice [6] and those lacking the Gα12/Gα13 and Rho pathways [15] in smooth muscle cells. The lack of LPA1 disrupts the endothelial barrier and results in increased vascular permeability in response to inflammatory stimuli in the lung [16] and the skin [17]. Conversely, LPA1 antagonists prevent inflammation in response to peritoneal injection of lipopolysaccharide [18]. Whether either a defect in smooth muscle or endothelial cell function accounts for the bleeding observed in the Lpar1−/− mice remains unknown. Knockout of both Lpa1 and Lpa2 increases the incidence of prefrontal hematomas [19], impairs the response to vascular injury [6], and results in the development of pulmonary hypertension with age [20]; the latter phenotype in not observed in mice with deficiency of either of the receptors alone. Together, these results suggest some redundancy or overlap between the 2 receptor systems. Likewise, LPA1 and LPA3 antagonists reduce arterial remodeling elicited by denudation injury [7] in mice, perhaps due to attenuated signaling through both G12/G13 and Gq/G11 signaling pathways, which appear to regulate vascular remodeling antagonistically. Lpar4-deficient mice display a genetic background-dependent defect in formation of vasculature. On the C57Bl/6 background, the mice develop hemorrhage and edema due to a maturation defect from lack of smooth muscle cell and pericytes recruitment vessels [21]. As described in more detail below, studies in zebrafish also support a role for several of the canonical LPA receptors in blood vessel formation. Additionally, LPA signaling through RAGE may also affect SMC function [13].