Syndecan Teams Up with Notch

Science Signaling  22 May 2012:
Vol. 5, Issue 225, pp. ec146
DOI: 10.1126/scisignal.2003245

Endothelial and smooth muscle cells communicate to ensure proper formation and function of vasculature. Notch proteins—which are transmembrane receptors that are cleaved during activation, producing an intracellular fragment, the NICD, that is a transcriptional regulator—are critical for cell fate determination and differentiation and play a role in angiogenic remodeling. Syndecans, transmembrane proteins that function as co-receptors for growth factor signaling, are also implicated in angiogenesis. Zhao et al. described the interaction of Notch3 and syndecan-2 to elucidate the signaling mechanisms responsible for communication between endothelial and smooth muscle cells. Coculture of human umbilical vein endothelial cells (HUVECs) with human aortic smooth muscle cells (HAoSMCs) induced expression of syndecan-2 mRNA in HAoSMCs, and this response was lost if Notch2 and Notch3 were both knocked down in HAoSMCs by small-interfering RNA (siRNA). Overexpression of NICD from Notch2 or Notch3 in HAoSMCs promoted syndecan-2 expression. In vivo, knockdown of Notch2 and Notch3 also decreased syndecan-2 expression in vascularized yolk sacs of mouse embryos. Coculture with HUVECs stimulated a Notch reporter gene in HAoSMCs, and this was attenuated when syndecan-2 was knocked down by siRNA, suggesting that syndecan-2 may also regulate Notch signaling. Coculture increased expression of several Notch3 target genes in HAoSMCs, and siRNA knockdown of syndecan-2 reduced their expression. However, overexpression of syndecan-2 alone in the absence of coculture conditions was not sufficient to drive expression of Notch3 target genes. Reciprocal coimmunoprecipitation experiments suggested that Notch3 and syndecan-2 interacted. These data suggest that syndecan-2 enhances Notch signaling in smooth muscle cells and that this may be a mechanism by which syndecan-2 promotes angiogenesis.

N. Zhao, H. Liu, B. Lilly, Reciprocal regulation of syndecan-2 and Notch signaling in vascular smooth muscle cells. J. Biol. Chem. 287, 16111–16120 (2012). [PubMed]