EphrinB2 Activation Enhances Vascular Repair Mechanisms and Reduces Brain Swelling After Mild Cerebral Ischemia

Abstract

Objective— Cerebral edema caused by the disruption of the blood–brain barrier is a major complication after stroke. Therefore, strategies to accelerate and enhance neurovascular recovery after stroke are of prime interest. Our main aim was to study the role of ephrinB2/EphB4 signaling in mediating the vascular repair and in blood–brain barrier restoration after mild cerebral ischemia occlusion/reperfusion. Approach and Results— Here, we show that the guidance molecule ephrinB2 plays a key role in neurovascular protection and blood–brain barrier restoration after stroke. In a focal stroke model, we characterize the stroke-induced damage to cerebral blood vessels and their subsequent endogenous repair on a cellular, molecular, and functional level. EphrinB2 and its tyrosine kinase receptor EphB4 are upregulated early after stroke by endothelial cells and perivascular support cells, in parallel to their reassembly during neurovascular recovery. Using both retroviral and pharmacological approaches, we show that the inhibition of ephrinB2/EphB4 signaling suppresses post-middle cerebral artery occlusion neurovascular repair mechanisms resulting in an aggravation of brain swelling. In contrast, the activation of ephrinB2 after brain ischemia leads to an increased pericyte recruitment and increased endothelial–pericyte interaction, resulting in an accelerated neurovascular repair after ischemia. Conclusions— We show that reducing swelling could result in improved outcome because of reduction in damaged brain tissue. We also identify a novel role for ephrinB2/EphB4 signaling in the maintenance of the neurovascular homeostasis and provide a novel therapeutic approach in reducing brain swelling after stroke.

Nogo-A targeted therapy promotes vascular repair and functional recovery following stroke

“…For example, viral overexpression of the positive guidance molecule Netrin1 promoted angiogenesis and long-term neurological recovery in a mouse model of transient focal ischemia (46). Also, activation of the guidance molecule ephrinB2 enhanced neurovascular repair and pericyte recruitment after brain ischemia (47). On the other hand, inhibition of the repulsive axonal guidance molecule Semaphorin 4D reduced BBB permeability as well as infarct volume and improved neurologic performance of rats after transient middle cerebral artery occlusion (48).…”

Regulator of G‐protein signaling 5 regulates the shift from perivascular to parenchymal pericytes in the chronic phase after stroke

“…The significant increase in perivascular pericytes in RGS5-KO mice not only resulted in higher pericyte coverage but also in improved vascular density and length. It has been shown that pericytes are important modulators of vascular stabilization (8–11). Our findings are supported by previous evidence in a tumor model demonstrating that loss of RGS5 results in vascular normalization due to pericyte maturation (40).…”

“…During the chronic phase of stroke, pericytes are essential to stabilize the remaining and newly formed blood vessels (8)(9)(10)(11), but vessel wall-derived pericytes have also been described to migrate into the injured parenchyma and contribute to scar-forming PDGFR-b + cells (4,5).…”

“…However, poststroke recovery during the chronic phase requires remodeling of the vasculature (6), a process that is essential for vascular repair and BBB restoration (7). The remodeling of the vasculature is closely associated with vessel stabilization by brain pericytes (8)(9)(10)(11). How this process is regulated is much less studied, and only a few molecular players behind poststroke vascular repair through pericytes have been identified (10)(11)(12)(13).…”

“…The remodeling of the vasculature is closely associated with vessel stabilization by brain pericytes (8)(9)(10)(11). How this process is regulated is much less studied, and only a few molecular players behind poststroke vascular repair through pericytes have been identified (10)(11)(12)(13). Especially, how the fate choice from vascular to scar-forming pericytes is regulated is not known.…”