From vascular sprouting to blood–brain barrier restoration: tip–stalk endothelial plasticity in post-stroke cerebrovascular repair

Ischemic stroke can trigger endogenous angiogenesis; however, newly formed vessels are often structurally immature, poorly perfused, and hyperpermeable, thereby failing to effectively restore blood–brain barrier (BBB) function. This indicates that vascular sprouting is not equivalent to functional vascular repair. During vascular sprouting, endothelial cells (ECs) that transiently acquire a tip-cell state occupy the leading edge of vascular sprouts, where they respond to hypoxic signals, vascular endothelial growth factor (VEGF) gradients, and extracellular matrix cues to guide sprout extension. Rather than representing fixed endothelial subpopulations, tip- and stalk-associated phenotypes are dynamic functional states that individual ECs can reversibly transition under the regulation of VEGF–Notch signaling, metabolic remodeling, and cell–cell interactions. This review examines the continuum of reparative cerebral angiogenesis from vascular sprouting to functional maturation, with particular emphasis on tip-cell states during cerebrovascular development and tip-cell-like endothelial states during post-stroke angiogenesis, and on their contributions to vascular sprouting, directed migration, endothelial rearrangement, and early vascular network patterning. It further distinguishes these early sprouting events from subsequent anastomosis, establishment of perfusion, endothelial maturation, and BBB restoration, while highlighting the functional coordination among these distinct but interconnected stages of vascular repair. In addition, this review discusses the coordinated contributions of pericytes, glial cells, the extracellular matrix, and hemodynamic cues, as well as the effects of inflammation, oxidative stress, matrix metalloproteinase activation, and endothelial senescence on vascular repair. By establishing an integrated framework spanning vascular sprouting, vascular maturation, and barrier restoration, this review emphasizes the need to shift therapeutic strategies from simply increasing vessel number toward promoting vascular normalization and functional BBB restoration after stroke.