During development, regional dips in oxygen levels serve as a signal that triggers the coordinated growth of heart muscle and coronary vessels, according to a study led by researchers at Weill Cornell Medicine. The findings, published online in the Proceedings of the National Academy of Sciences, could point toward innovative approaches for treating cardiovascular conditions that lead to heart failure.
“The signaling pathways that direct the development of this remarkable organ are also affected in pathological conditions,” said Dr. Michael Harrison, assistant professor of cell and developmental biology and a member of the Cardiovascular Research Institute of Weill Cornell Medicine. “Interventions that target these signals or the cells that produce them could potentially change the trajectory of disease or slow its progression.”
Looking for the Leader
As a postdoctoral fellow, Dr. Harrison explored how coronary vessels influence cardiac regeneration in zebrafish, a useful model for studying heart development and repair. “Looking through the literature, I realized that we knew very little about how coronary vessels develop in the first place,” he said.
One of the biggest mysteries was: what drives their growth—and how is that expansion synchronized with that of the muscle tissue they serve? “Initially we thought that there would be direct crosstalk between the two,” Dr. Harrison said. Either the muscle secretes signals that attract developing vessels—or the vessels produce signals that promote muscle growth.
To find out which cell type leads the charge, Isaac Bakis—a technician in the Harrison lab and the paper’s second author—performed live-cell imaging analyses using methods developed with collaborators at the University of Southern California. “But we saw no clear leader-follower relationship,” said Dr. Harrison. Although the two cell types expanded coordinately across the developing heart, he said, “sometimes muscle arrived first, sometimes the vessels.”
That got the team thinking that maybe both were responding to cues coming from a third type of cell. Dr. Ku-Chi Tsao, a postdoctoral researcher in the Harrison lab, looked at a layer of cells called the epicardium that surrounds the organ and supports its developing vasculature. In collaboration with Dr. Jingli Cao, an epicardium expert and associate professor of cell and developmental biology at Weill Cornell and a member of its Cardiovascular Research Institute, they discovered that the regions of coordinated outgrowth correspond with areas where oxygen is low. When epicardial cells detect this hypoxia, they activate a suite of genes that generates signals that orchestrate the expansion of both muscle and vasculature.
A Self-Balancing System
The program operates as a self-limiting feedback loop. If muscle growth outstrips expansion of the oxygen-bearing vessels, hypoxia will activate the system and stimulate vasculature growth. When the vessels bring in a fresh supply of oxygenated blood, they dampen the signal, allowing muscle and vasculature to balance their expansion and optimize cardiac function.
In zebrafish mutants that fail to develop coronary vessels, the heart muscle shows excessive expansion and becomes unusually thick and stiff — measurements the Harrison lab made in collaboration with Dr. Jonathan Butcher, the Joseph Newton Pew Jr. Professor in Engineering at the Meining School of Biomedical Engineering at Cornell’s Ithaca campus. Destroying the epicardial cells blocks this hyperexpansion, confirming their role in orchestrating the program.
Such a hypoxia-responsive system could play a part in certain types of heart failure, which display a similar pattern of muscle stiffening and vascular disruption. “The genes we identified are conserved across species and some even play a known role in disease pathology,” said Dr. Harrison. “To figure out what they might be doing in mammals—where there will probably be some added complexity—we need to tease apart what they’re acting on, which are the most important and which can potentially be targeted.”
