The formation of functional blood vessel after cardiac ischemia is critical to restore cardiac function and improve patient prognosis. However, current revascularization strategies have been largely ineffective in establishing a stable, mature vascular network capable of providing adequate perfusion 1,2.
A significant obstacle to the development of effective revascularization therapies is the poor understanding of the complex molecular, cellular, and structural cues essential for forming a hierarchical blood vessel network. The elucidation of the pathways that orchestrate arteriovenous specification in coronary vessels would provide important insight to achieve this goal.
In this context, Cano et al. provide a significant advancement in the understanding of the mechanisms governing coronary arterialization, focusing on the origin and characterization of coronary prearterial cells. Leveraging three-dimensional analysis, single-cell transcriptomics, and lineage tracing, the authors unveil the patterns of angiogenic sprouting and the emergence and distribution of prearterial cells during coronary vasculature formation. These cells penetrate the myocardial wall from both the subepicardial plexus and the endocardium and are characterized by Cxcr4- and Esm1-expressing tip cells. This new angiogenic front adds to the one that progresses superficially within the subepicardium and is characterized by Apln-expressing tip cells, previously described by others group 3-5.
At the initial stages of coronary sprouting, there is no overlap between Apln-expressing and Esm1-expressing tip cells, indicating these two subpopulations are mutually exclusive. This is in contrast with the traditional concept that considers Apln and Esm-1 as common, canonical tip cell markers 6. Differential gene expression analysis reveals an enrichment of hypoxia-related genes in Esm1-expressing intramyocardial tip cells, consistent with a decreasing gradient in oxygen tension from the subepicardium to the myocardium 7. This suggests that hypoxia might be a key regulator of Esm1-positive tip cell function and arterial specification.
By examining different developmental stages, the authors observed that prearterial cells persist from embryonic stages through adulthood and they can be reactivated in response to myocardial ischemia, forming new coronary arteries. This indicates a conserved mechanism of tip cell-driven arterial specification, which is present in humans.
In conclusion, Cano et al.'s study significantly advances our understanding of coronary arterialization mechanisms. The identification of intramyocardial tip cells as key drivers of arterial specification opens new possibilities for developing therapies that specifically target these cells to enhance revascularization efforts. Future research might focus on the therapeutic modulation of the Esm1-Cxcr4 signaling axis to harness prearterial cells to form functional arteries in the ischemic heart.
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