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Introduction: The leptomeningeal collaterals (LMCs) are specialized brain surface arterioles that interconnect the distalmost arterioles (DMAs) of the major cerebral arteries. In normal conditions, flow in LMCs is negligible. However, during ischemic stroke, the LMCs provide a vital route for rescue blood flow from neighboring vessel territories, thereby lessening ischemic injury and improving outcome. With sustained flow, the LMCs rapidly remodel to further increase perfusion capacity. The LMCs differ in function and molecular composition compared to DMAs, however, a comprehensive transcriptional signature of these two vessel types is not available. Therefore, we developed methods to identify and isolate LMCs and DMAs from pig brain for subsequent unbiased RNAseq analysis. Methods: Duroc pigs were used to due to their larger vascular anatomy and gyrencephalic brains. We first mapped the cerebral vasculature and location of LMCs using blue dye infusion (surface vessel tracing) and BaSO4 microparticle infusion (3D microCT imaging). Having established location of LMCs, we infused an RNAlater/blue ink solution to facilitate vessel visualization and RNA stabilization during dissection. Harvested LMCs and DMAs were pooled by type and processed for RNAseq and analysis by R. Results: RNAseq analysis of LMCs and DMAs revealed 349 differentially expressed genes (DEGs) (adjusted p value < 0.05, fold change > 0.5), of which 241 were upregulated and 108 were down regulated in LMCs. Gene ontology (GO) analysis showed upregulation of biological processes including “vasculature development”, “sprouting angiogenesis”, “angiogenesis”, and “regulation of smooth muscle cell proliferation” in the LMC group. Angiogenesis related genes ( Cldn5 , Kdr , Vegfc , and Vwf ) were markedly upregulated in LMCs compared to DMAs (1.75 to 2.75 fold). In contrast, “extracellular matrix organization” and “positive regulation of smooth muscle cell migration” were among the most downregulated biological processes in LMCs. Conclusions: Our unbiased RNAseq approach revealed numerous DEGs between LMCs and DMAs. Interestingly, GO analysis revealed a proangiogenic signature in LMCs, which may shed new light on how they are able to rapidly remodel following ischemic stroke.