<p>Cerebral small vessel disease (cSVD) associated with the occlusion of small penetrating arterioles leading to multifocal microinfarcts, constitutes a common cerebral microangiopathy . Dickkopf-1 (DKK1), a potent inhibitor of the canonical Wnt pathway, plays key roles in regulating neurovascular and immune responses . DKK1 levels are reported to be increased in cerebrovascular diseases, correlating with poor prognosis. Herein, we aimed to investigate the contribution of DKK1 elevated levels to the pathobiology of cSVD associated with microinfarctions. This was achieved using a transgenic mouse model that enables a conditional tissue-specific induction of DKK1. cSVD was induced via intravascular injection of micro-emboli to occlude penetrating arterioles. Our results indicate that the circulating levels of endogenous DKK1 are increased after cSVD and remain steadily elevated before progressively returning to basal levels. DKK1 conditional induction with respect to its temporal endogenous regulation after cSVD exacerbates vascular permeability and alters immediate cerebrovascular reactivity, outlining deregulation of the neurovascular functions. Furthermore, DKK1 induction correlates with a progressive neuronal loss and an impaired neurogenesis after cSVD. We show that DKK1 elevated levels are associated with attenuation of myeloid cell recruitment to the lesion sites, accompanied with a persistent polarization of monocytes in the blood circulation towards a pro-inflammatory phenotype. Notably, we reveal that DKK1 elevated levels for a prolonged period after cSVD are accompanied with pathological changes that remain partially persistent despite delayed normalization of its expression. Our study suggests that circulating DKK1 exacerbates the pathobiology of cSVD associated with microinfarctions, outlining its potential as a prognostic marker and a therapeutic target.</p> Graphical Abstract