Chinese Researchers Identify How the Heart Builds Its Own Bypass Vessels

The mechanism by which the heart builds new vessels to bypass blocked blood vessels has been identified. Contrary to the prevailing theory, a study found that new bypass vessels arise primarily from capillaries, not existing arteries.

On Aug. 21 (local time), the international journal Science published online a collaborative study by a team led by Zhou Bin (周斌) of the Center for Excellence in Molecular Cell Science at the Chinese Academy of Sciences and a team led by Professor Lü Ailan (呂愛蘭) of the Chinese University of Hong Kong.

The researchers traced the cellular origins of new coronary collateral (bypass) vessels that form after myocardial infarction. When a coronary artery is blocked, downstream heart muscle tissue becomes necrotic due to a lack of oxygen. Collateral vessels act as “natural bypasses,” routing blood around the blockage.

Until now, the scientific community had believed that collateral vessels form as existing small arteries expand and remodel. The leading hypothesis about the origin of new collateral vessels was “arterial reassembly,” in which existing arterial endothelial cells migrate, proliferate and reorganize.

However, the researchers said that the existing genetic tracing system underlying this hypothesis also labeled some capillary endothelial cells, leading to errors in interpretation. The team therefore developed a high-precision tracing tool based on dual recombinases and a synNotch system that records cell contact.

Analysis using the new tools showed that most new collateral vessels originated from capillary endothelial cells, while only a small number came from existing arterial endothelial cells. The researchers said that removing capillary-derived collateral vessels worsened myocardial fibrosis and enlarged the damaged area, indicating that these vessels play a key role in restoring blood flow and regenerating the heart.

Mechanistic studies identified vascular endothelial growth factor A (VEGFA) as a key regulator. The researchers said that temporarily increasing VEGFA expression using modified messenger RNA (modRNA) technology promoted the formation of functional arteries, reduced cardiac scarring and improved heart function.

The researchers identified a signaling pathway in which VEGFA activates the transcription factor YY1, which recruits the histone methyltransferase SETD1A to induce H3K4 trimethylation. This, in turn, promotes transcription of HES1, a downstream factor in Notch signaling, converting capillaries into arteries.

Zhou Bin and Professor Lü Ailan are co-corresponding authors. The researchers said the findings redefine the biological basis of coronary collateral circulation and point to a new target for treating ischemic heart disease.