A new role of lipid receptors in vascular and cardiac morphogenesis

Diverse classes of molecules regulate cell migration, one of the most fundamental processes in development and disease. In the vascular system, smooth muscle cell migration mediated by the PDGF-B pathway (1) is required for both normal blood vessel formation during development and pathogenesis of vascular diseases. In this paracrine signaling pathway, endothelial cells secrete PDGF-B, which acts on the PDGF-β receptor expressed on the surface of smooth muscle cell precursors and initiates the migration of the latter cells toward endothelial cells during angiogenesis. In this issue of the JCI, Liu et al. implicate another receptor and another class of mediator — bioactive glycolipids — in smooth muscle cell migration in the mouse (2). Remarkably, this same class of molecule was recently shown to mediate the migration of cardiac muscle progenitor cells during the initial formation of the heart tube in zebrafish development (3). Together, these two studies establish the presence of a common pathway, mediated by receptors for sphingosine-1-phosphate (S1P), underlying both smooth muscle and cardiac muscle migration during vascular and cardiac development (Figure ​(Figure11). Figure 1 New roles of lipid receptors in cardiac and vascular development. Receptors for S1P are critical for the migration of cardiac muscle precursors and smooth muscle cells during heart tube formation and blood vessel formation, respectively. See the text ... In the present study, Liu et al. (2) address the putative biological functions of one of the S1P receptors, Edg-1, by generating knockout mice for its gene. Edg-1 belongs to a family of G protein–coupled receptors for S1P or lysophosphatidic acid (4, 5). Edg-1 is a specific receptor for S1P and interacts directly with the Gi pathway. Targeted mutation of Edg-1 resulted in embryonic lethality (2), but the most intriguing feature of the Edg-1 knockout phenotype is the apparent lack of normal layers of smooth muscles surrounding endothelial cells of vessels (2). Interestingly, smooth muscle cells are clustered to the ventral side of the vessels and fail to surround the endothelial lumen of the vessels in a uniform fashion. Smooth muscle cell precursor cells have been thought to be recruited from any direction in the vessel’s vicinity (1). However, this polarized clustering of smooth muscle cells in Edg1 mutant embryos suggests an alternative model in which smooth muscle cells are recruited in a unidirectional manner (6, 7) and only later spread to surround the endothelium. This unidirectional recruitment is not understood, but it might be explained by an asymmetrically distributed chemoattractant gradient or by the presence of a critical adhesive factor on the ventral side of the developing vessel. In PDGF-B–deficient mice, in contrast, pericytes (contractile cells for capillaries equivalent to smooth muscle cells for larger vessels) are not unevenly distributed but are actually absent from vessels (8). This difference suggests the following model for the smooth muscle formation in developing vessels (Figure ​(Figure2):2): PDGF-B, secreted by endothelial cells undergoing angiogenesis, mediates the recruitment of smooth muscle precursors toward the immediate vicinity of the endothelial cells, where they accumulate in an asymmetric fashion. Once the smooth muscle precursors are immediately adjacent to endothelial cells, they are induced to differentiate to mature smooth muscle cells via signaling pathways including TGF-β, endoglin, and SMADs (1, 9–11). Following the formation of a complete vascular lumen by endothelial cells, S1P mediates the migration of smooth muscle cells either directly or indirectly to surround the endothelial layer. Because smooth muscle cell migration goes awry in many types of vascular disease (12, 13), this model could have profound clinical as well as biological implications. It is conceivable that the same or a related lipid receptor signaling pathway is critically involved in or could be exploited to treat human diseases. Figure 2 Sequential roles of PDGF-B/TGF-β/S1P in smooth muscle infiltration into vessels. During angiogenesis, endothelial cells that are yet to form a mature vascular lumen secrete PDGF-B to recruit smooth muscle precursor cells to their immediate vicinity. ...