Coronary Artery Formation Is Driven by Localized Expression of R-spondin3

Coronary arteries are essential to support the heart with oxygen, and coronary heart disease is one of the leading causes of death worldwide. The coronary arteries form at highly stereotyped locations and are derived from the primitive vascular plexus of the heart. How coronary arteries are remodeled and the signaling molecules that govern this process are poorly understood. Here, we have identified the Wnt-signaling modulator Rspo3 as a crucial regulator of coronary artery formation in the developing heart. Rspo3 is specifically expressed around the coronary stems at critical time points in their development. Temporal ablation of Rspo3 at E11.5 leads to decreased β-catenin signaling and a reduction in arterial-specific proliferation. As a result, the coronary stems are defective and the arterial tree does not form properly. These results identify a mechanism through which localized expression of RSPO3 induces proliferation of the coronary arteries at their stems and permits their formation. [Display omitted] •Rspo3 is expressed in angiogenic regions around developing coronary arteries•Rspo3 promotes localized arterial proliferation through Wnt/β-catenin signaling•Rspo3 deletion leads to defective coronary stem and improper arterial tree formation Coronary arteries supply the heart with blood, and coronary diseases are one of the leading causes of death worldwide. Da Silva et al. find that RSPO3 is specifically expressed around the developing stems of the left and right coronaries, where it promotes their formation by stimulating arterial-specific proliferation through Wnt/β-catenin signaling.