Abstract
The regulation of bone vasculature by chronic diseases, such as heart failure is unknown. Here, we describe the effects of myocardial infarction and post-infarction heart failure on the bone vascular cell composition. We demonstrate an age-independent loss of type H endothelium in heart failure after myocardial infarction in both mice and humans. Using single-cell RNA sequencing, we delineate the transcriptional heterogeneity of human bone marrow endothelium, showing increased expression of inflammatory genes, including IL1B and MYC, in ischemic heart failure. Endothelial-specific overexpression of MYC was sufficient to induce type H bone endothelial cells, whereas inhibition of NLRP3-dependent IL-1β production partially prevented the post-myocardial infarction loss of type H vasculature in mice. These results provide a rationale for using anti-inflammatory therapies to prevent or reverse the deterioration of bone vascular function in ischemic heart disease.
Highlights
The regulation of bone vasculature by chronic diseases, such as heart failure is unknown
Coinciding with the decrease of type H endothelium, long-term hematopoietic stem cells (LT-HSC) significantly increased in mice during the development of post-infarction heart failure (Fig. 1b and Supplementary Fig. 3a)
The reduction of type H bone endothelial cells (EC) seems to be strongly associated with inflammatory responses, as evidenced by the induction of IL-1β in type H vessels, preceding their loss after myocardial infarction (MI)
Summary
The regulation of bone vasculature by chronic diseases, such as heart failure is unknown. Endothelial-specific overexpression of MYC was sufficient to induce type H bone endothelial cells, whereas inhibition of NLRP3-dependent IL-1β production partially prevented the post-myocardial infarction loss of type H vasculature in mice. These results provide a rationale for using anti-inflammatory therapies to prevent or reverse the deterioration of bone vascular function in ischemic heart disease. This study shows that post-MI heart failure drives a loss of type H bone ECs, which is associated with a pronounced inflammatory response and pyroptosis This change appears to be dependent upon IL-1β and MYC signaling, though independent of B2adrenergic activity. This investigation provides a rationale for use of anti-inflammatory therapies to prevent the deterioration of the bone vascular niche
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