Pericytes, cells that surround blood vessels, have been described as “bumps on a log”—not because they are inactive or useless, but because they protrude, bump-like, from capillary walls. In fact, pericytes are already known to be useful. They help regulate the formation and function of blood vessels. But it is also true that these cells could become even more useful. If pericytes had the right incentives, they might reverse tissue damage caused by heart attacks, possibly lessening the need for coronary bypass operations. Also, pericytes might—again, given the right incentives—slow the growth and spread of cancer.
In both cases, cardiovascular disease and cancer, the “right incentives” might involve leptin, the so-called satiety hormone. Leptin at high levels may cause pericytes favor angiogenesis, the growth of new blood vessels, whereas leptin at low levels may cause pericytes to disfavor angiogenesis. Enhancing angiogenesis could promote recovery from heart attacks; curbing angiogenesis could starve tumors of oxygen and nutrients.
New findings suggest that leptin and pericyte activity are linked. These findings, uncovered by scientists based at the University of Bristol, appeared July 14 in the journal Scientific Reports, in an article entitled, “The adipokine leptin modulates adventitial pericyte functions by autocrine and paracrine signaling.” The article focuses on a type of pericyte called the adventitial pericyte (APC) and explores the role of the adipokine leptin (LEP) in the regulation of human APC biological functions.
“We show for the first time that APCs secrete abundant levels of LEP under hypoxia,” wrote the article’s authors. “APC-derived LEP exerts important regulatory roles in APC growth, survival, migration, and promotion of endothelial network formation.”
The University of Bristol team, led by Paolo Madeddu, professor of experimental cardiovascular medicine, noticed that the levels of secreted LEP predict the angiogenic activity of APC transplantation in a murine model of peripheral ischemia. According to Prof. Madeddu and colleagues, this observation suggests that “heterogeneity in LEP expression and secretion may influence the reparative proficiency of APC therapy.”
“Moreover,” the scientists added, “we found that the expression of the Lepr gene is upregulated on resident vascular cells from murine ischemic muscles, thus providing a permissive milieu to transplanted LEP-expressing APCs.
Importantly, Prof. Madeddu’s team found that pericytes produced 40 times more leptin when exposed to low levels of oxygen and that this continued until oxygen levels returned to normal. This may help tissues to build more blood vessels to increase blood flow and oxygen supply. Together with other findings, the research shows that leptin has several important actions which encourage new blood vessel growth in areas where tissues are deprived of oxygen.
In most cases, a heart attack is when a coronary artery becomes blocked and the resulting lack of blood supply to the heart muscle can lead to a damaged heart. Prof. Madeddu's team has shown that by stimulating the growth of new blood vessels, pericytes have the potential to restore blood supply to damaged heart muscle after a heart attack.
One of the current treatments for heart attack is coronary artery bypass surgery. This uses blood vessels from the leg, or elsewhere in the body, to bypass the blocked artery and improve blood flow to the heart muscle. This is invasive and major surgery, with a long recovery time. In the longer term, these findings may help in the development of an alternative treatment to major surgery for heart attack patients.
“This new discovery could have important implications for the treatment of heart attacks, which is when a main coronary artery gets blocked, but also cancer,” said Prof. Madeddu. “These results reveal a new signaling mechanism that may have a far-reaching and significant impact on cardiovascular regenerative medicine.”
“Increasing leptin in pericytes in a damaged heart might help it to heal faster, whereas blocking the production of leptin in cancerous pericytes might starve the tumor of nutrients and force it to shrink.”
“Our search for an association between LEP and therapeutic outcomes was not intended to disclose a cause-effect relationship,” noted the authors of the current paper. “We have previously shown that numerous paracrine factors contribute to the therapeutic action of human APCs.
“Our in vivo study represents a small-scale project, whose aim was to provide initial proof of principle for the in vitro findings, thus supporting subsequent larger validation studies prior to guided therapeutic applications of APCs into human subjects. The finding that ischemia induces the expression of the murine Lepr in resident vascular cells suggests favorable environmental conditions to the angiogenic action of LEP-expressing APCs.”