Role for Notch1 signaling in ischemic stroke‐induced endothelial cell dysfunction

Abstract

Notch signaling plays a major role in cell fate decisions during vascular development in vertebrates. We have recently shown that mice transgenic for antisense Notch and mice treated with gamma‐secretase inhibitors have reduced damage to brain cells and improved functional outcome in a model of focal ischemic stroke. Here we use human microvascular endothelial cells (HMECs), mouse brain endothelial cells (MBECs) and in vivo models of ischemicstroke to elucidate roles for Notch signalingin ischemic stroke‐induced endothelial dysfunction. Preliminary data show that Notch1 and the Notch ligand Jagged expression increase during the first few hours in glucose deprivation (GD) and oxygen and glucose deprivation (OGD) conditions in both HMECs and MBECs. Immunoblot analysis also showed increased expression of Notch intracellular domain (NICD) in response to OGD in MBECs. We also observed increased levels of the Notch signaling‐induced transcription factors (Hes) in response to GD and OGD. Finally, we found that treatment with the gamma‐secretase inhibitor DAPT reduces Notch signaling‐mediated gene expression after OGD condition in MBECs. We are currently studying the role of increased Notch signaling in endothelial dysfunction in a mouse model of ischemic stroke.