notch pathway modulation on bone marrow-derived vascular precursor cells regulates their angiogenic and wound healing potential来源于血管前体细胞的notch通路调制在骨调节血管生成和伤口愈合的潜力.pdfVIP

Notch Pathway Modulation on Bone Marrow-Derived Vascular Precursor Cells Regulates Their Angiogenic and Wound Healing Potential 1,2 1,2 ˆ 1,2 ´ 1,2,3 Francisco Caiado , Carla Real , Tania Carvalho , Sergio Dias * 1 Angiogenesis Laboratory, CIPM, Portuguese Institute of Oncology, Lisbon, Portugal, 2 Instituto Gulbenkian Ciencia, Oeiras, Portugal, 3 Instituto de Medicina Molecular, Lisbon, Portugal Abstract Bone marrow (BM) derived vascular precursor cells (BM-PC, endothelial progenitors) are involved in normal and malignant angiogenesis, in ischemia and in wound healing. However, the mechanisms by which BM-PC stimulate the pre-existing endothelial cells at sites of vascular remodelling/recovery, and their contribution towards the formation of new blood vessels are still undisclosed. In the present report, we exploited the possibility that members of the Notch signalling pathway, expressed by BM-PC during endothelial differentiation, might regulate their pro-angiogenic or pro-wound healing properties. We demonstrate that Notch pathway modulates the adhesion of BM-PC to extracellular matrix (ECM) in vitro via regulation of integrin alpha3beta1; and that Notch pathway inhibition on BM-PC impairs their capacity to stimulate endothelial cell tube formation on matrigel and to promote endothelial monolayer recovery following wounding in vitro. Moreover, we show that activation of Notch pathway on BM-PC improved wound healing in vivo through angiogenesis induction. Conversely, inoculation of BM-PC pre-treated with a gamma secretase inhibitor (GSI) into wounded mice failed to induce angiogenesis at the wound site and did not promote wound healing, presumably due to a lower frequency of BM-PC at the