Sphingolipid signaling in the regulation of vascular network assembly

We have recently established the critical importance of sphingosine‐1‐phosphate (S1P) signaling in the process of vasculogenesis. Specifically, S1P signaling influences behaviors of angioblasts and early endothelial cells (e.g., motility) that lead to expansion of embryonic vascular networks. Our current investigations focus on establishing a mechanistic basis for the motility‐related effects of S1P on angioblasts and early endothelial cells required for blood vessel formation. First, using qPCR analysis we found that S1P receptors S1P1, S1P2, S1P3, Gpr3 and Gpr63 are expressed by angioblasts and early endothelial cells with S1P1 and S1P2 expressed at highest levels. Consistent with these findings are those showing that embryonic vascular network formation is sensitive to pertussis toxin, a known inhibitor of S1P1 and S1P2‐mediated signaling. We have also established that the physiological carrier of S1P, high‐density lipoproteins (HDL), can mediate the expansion of embryonic vascular networks in a pertussis toxin‐sensitive manner. Finally, we have found that S1P acts as a modulator of filopodial extension by tip cells engaged in vascular network formation. Furthermore, that the effects of S1P on filopodial extension were found to be dependent on expression of the gap junction protein, connexin 43.