Dach1 Extends Artery Networks and Protects Against Cardiac Injury

Abstract

Rationale: Coronary artery disease (CAD) is the leading cause of death worldwide, but there are currently no methods to stimulate artery growth or regeneration in diseased hearts. Studying how arteries are built during development could illuminate strategies for re-building these vessels during ischemic heart disease. We previously found that Dach1 deletion in mouse embryos resulted in small coronary arteries. However, it was not known whether Dach1 gain-of-function would be sufficient to increase arterial vessels and whether this could benefit injury responses. Objective: We investigated how Dach1 overexpression in endothelial cells affected transcription and artery differentiation, and how it influenced recovery from myocardial infarction (MI). Methods and Results: Dach1 was genetically overexpressed in coronary endothelial cells (ECs) in either developing or adult hearts using ApjCreER. This increased the length and number of arterial end branches expanded arteries during development, in both the heart and retina, by inducing capillary ECs to differentiate and contribute to growing arteries. Single-cell RNA sequencing (scRNAseq) of ECs undergoing Dach1-induced arterial specification indicated that it potentiated normal artery differentiation, rather than functioning as a master regulator of artery cell fate. ScRNAseq also showed that normal arterial differentiation is accompanied by repression of lipid metabolism genes, which were also repressed by Dach1. In adults, Dach1 overexpression did not cause a statistically significant change artery structure prior to injury, but increased the number of perfused arteries in the injury zone post-MI. Conclusions: Our data demonstrate that increasing Dach1 is a novel method for driving artery specification and extending arterial branches, which could be explored as a means of mitigating the effects of CAD.

Mapping the developing human cardiac endothelium at single-cell resolution identifies MECOM as a regulator of arteriovenous gene expression

“…Velocity analysis also predicted a likely transition of both capillary EC populations towards an arterial EC fate (Figures 3A and S3B). This is an agreement with previous reports of developmental arterial remodelling in mouse [7][8][9] .…”

“…Trajectory inference analysis also revealed subsequent arterial specification of capillary EC. This predicted cellular transition in the human fetal heart was also recently identified by Phansalkar el al 19 , thus collectively providing human relevance to current understanding of coronary artery development derived from murine studies [7][8][9] . However, in addition to confirming the upregulation of known mediators of arterial specification such as HEY1 40 and SOX17 53 , MECOM was also identified as having a role in the establishment of an arterial EC identity.…”

“…However, further studies simultaneously targeting the expression of characterised arterial EC regulators is required to determine the position of MECOM within the hierarchal network of arteriovenous regulators. Previous findings in mouse demonstrated overexpression of arterial EC regulator Dach1 resulted in an increase in perfused arteries following myocardial infarction 8 . Our finding from human data suggesting MECOM may function to maintain the transcriptional identity of arterial EC highlights it as a prime therapeutic candidate to drive arterialisation in cardiovascular disease.…”

“…Expression of DACH1 was found to peak within the IMNT + capillary cluster before gradually decreasing again within the arterial population (Figure S4C). Previous studies have identified Dach1 as a driver of developmental arterial remodelling in murine cardiac development 8,9 .…”

“…Recent studies have elegantly mapped the remodelling of the immature coronary EC plexus in mouse cardiac development, including identification of a role for the transcription factor Dach1 in potentiating developmental arterial remodelling [7][8][9] . However, given that these advances in our understanding of coronary vascular development primarily originate from murine lineage tracing studies, the relevance of these findings for human cardiac development remains largely unknown.…”