Ischemic stroke is one of the most common types of central nervous system injuries, and among the leading causes of morbidity in US adults. There undoubtedly remains few available treatment options, none of which is effective for tackling this debilitating vascular occlusive disease. Vascular occlusion has been shown to induce the immediate active remodeling of pre-existing collateral arterioles (arteriogenesis) into functional conduits for oxygen, nutrients and drug delivery. Although, arteriogenesis is an active therapeutic target for enhancing stroke recovery, the mechanism(s) regulating this response remain elusive. The research objectives in this pre-doctoral application focus on the cell autonomous role of Eph receptor (EphR) signaling in limiting the arteriogenic response following permanent middle cerebral artery occlusion (pMCAO). In support of our objectives we have determined there is a significant increase in arteriole remodeling, greater recovery of cerebral blood flow and reduced infarct in the absence of EphR on Tie2-expresssing cells after pMCAO. Based upon extensive preliminary data, we hypothesize that EphR profoundly limits injury-induced arteriogenesis, blood flow restoration and tissue recovery by suppressing the pro-arteriogeneic response via regulation of key events on endothelial cells. We will test our hypothesis using cell-specific loss-of-function and reverse of function infusion approaches. These studies will shed light on a novel mechanism regulating cerebrovascular arteriogenesis and will provide support for future strategies aimed at targeting therapeutic enhancement of this adaptive process to improve neural functional recovery.
The proposed studies focus on an essential but understudied area of research involving arteriole remodeling in the injured adult brain, a biological system known for limited repair. The overall goal is to improve our understanding of the constraints placed on the cerebrovascular network in response to vascular occlusion and whether modulation of EpR signaling could impact neurovascular restoration following stroke. Identifying key pathways involved in orchestrating the events necessary for neural recovery have enormous potential for improving the lives of individuals suffering from stroke and other neurological conditions.
| Okyere, Benjamin; Creasey, Miranda; Lebovitz, Yeonwoo et al. (2018) Temporal remodeling of pial collaterals and functional deficits in a murine model of ischemic stroke. J Neurosci Methods 293:86-96 |
