Molecular control of capillary guidance
Zusammenfassung der Projektergebnisse
Sprouting of developing blood vessels is mediated by specialized motile endothelial cells localized at the tips of growing capillaries. Following behind the tip cells, endothelial stalk cells form the capillary lumen and proliferate. Expression of the Notch ligand Delta-like4 (Dll4) in tip cells suppresses tip cell fate in neighboring stalk cells via Notch signaling. In dll4+/- mouse mutants, most retinal endothelial cells display morphological features of tip cells. Using transcriptome analysis of retinal endothelial cells isolated from dll4+/- and wild type mice, three clusters of tip cell-enriched genes were identified, encoding extracellular matrix degrading enzymes, basement membrane components and secreted molecules. Secreted molecules ESM-1, angiopoietin 2 and apelin bind to cognate receptors on endothelial stalk cells. Knockout mice and zebrafish morpholino knockdown of apelin showed delayed angiogenesis and reduced proliferation of stalk cells expressing the apelin receptor APJ. Thus, tip cells regulate angiogenesis via matrix remodeling, production of basement membrane and release of secreted molecules, some of which regulate stalk cell behavior.
Projektbezogene Publikationen (Auswahl)
- Identification and functional analysis of endothelial tip cell-enriched genes. Blood. 2010 Nov 11;116(19):4025-33
del Toro R, Prahst C, Mathivet T, Siegfried G, Kaminker JS, Larrivee B, Breant C, Duarte A, Takakura N, Fukamizu A, Penninger J, Eichmann A
- ALK1 Signaling Inhibits Angiogenesis by Cooperating with the Notch Pathway. Dev Cell. 2012 Mar 13;22(3):489-500
Larrivée B, Prahst C, Gordon E, Del Toro R, Mathivet T, Duarte A, Simons M, Eichmann A
