CCL2/CCR2 signaling-mediated microglial migration leads to cerebral small vessel dysfunction in chronic hypertension model rats

Abstract

Microglia are cerebral immune cells that maintain brain homeostasis; those that are juxtaposed to vessels are sometimes called vessel-associated microglia (VAM). Recent studies have indicated a role for VAM in maintaining blood–brain barrier integrity in different stages of diseases such as ischemic stroke and systemic inflammatory disease. Hypertension is a major cause of cerebral small vessel disease (CSVD) in humans. Recently, several reports reported that microglial activation in hypertensive animal models and our previous report indicated the increase in VAM from the early stage of chronic hypertension. However, the precise involvement of VAM in hypertensive CSVD remains unclear. In the present study, we used a deoxycorticosterone-acetate-salt chronic hypertensive rat model to demonstrate that signaling via CC motif chemokine ligand 2 (CCL2) and its receptor CC chemokine receptor type 2 (CCR2) is crucial for the increase in VAM. This signaling was associated with microglial migration toward vessels at the early disease stage. Moreover, the inhibition of this signaling resulted in reduced VAM numbers and the preservation of astrocytic endfeet in the late disease stage. Overall, CCL2/CCR2 signaling may be a trigger for microglial migration, leading to the development of CSVD, during chronic hypertension. This signaling is therefore a potential target for future preventive treatments.