In vascular cell experiments, membranes from lysed red blood cells trigger new capillary growth through ATP, and in patients with peripheral artery disease the weakened signal is restored by an existing drug

In vascular cell experiments, membranes from lysed red blood cells trigger new capillary growth through ATP, and in patients with peripheral artery disease the weakened signal is restored by an existing drug

In a paper published on 25 September in the journal Angiogenesis, cardiologists at the University Medical Center Mainz, led by Katrin Schäfer, showed that hemoglobin-free membranes from lysed red blood cells reprogram vascular wall cells and trigger the growth of new capillaries. The cause is ATP from the red blood cell membrane: acting through two receptors, it activates an inflammatory and reparative response in endothelial cells. In patients whose vessels cannot sprout new capillaries, this mechanism is weaker, but an existing drug restored it.

Hemorrhage into the vessel wall and the breakdown of red blood cells within it were long regarded as consequences of an already diseased vessel, not as a cause of changes in it. The hypothesis came from a well-established observation: red blood cells release ATP upon destruction, and ATP regulates vascular tone. This suggested that hemorrhage itself might serve as a repair signal. The idea held up: on contact with vascular wall cells (endothelium), such membranes altered the activity of 113 genes within two hours, switching on the vascular growth factor VEGF among them. In a 3D model, this treatment drove endothelial cells to sprout as many new vascular branches as VEGF itself, while also accelerating their proliferation and migration.

A control experiment ruled out the obvious suspect: purified heme, the iron-containing component of hemoglobin typically blamed for vascular damage, did not produce this growth response. The actual driver turned out to be ATP, the cell's energy currency. ATP engages two endothelial receptors: the fast-acting P2X7 activates the inflammatory hub NFκB, and the slower P2Y11 raises levels of the second messenger cAMP. Both signals converge on the protein NR4A1, which dampens inflammation and switches on vascular growth genes together with the enzyme PFKFB3, a metabolic switch that redirects the cell's metabolism toward vessel construction.

What the body routinely treated as debris after hemorrhage turned out to be a signal to rebuild.

The finding was tested in people with peripheral artery disease, a condition in which leg vessels cannot sprout new capillaries when blood supply falls short, causing pain on walking and, in severe cases, leading to amputation. The diagnosis becomes sharply more common with age: according to a large international estimate, it is found in 5.3% of people aged 45 to 50 and in 18.6% of people aged 85 to 90. Red blood cell membranes from these patients activated VEGF and PFKFB3 genes less effectively than membranes from healthy age-matched donors, but rolipram, a blocker of PDE4 (the enzyme that degrades cAMP), restored the response to the level seen in healthy donors. A clinical precedent exists as well: cilostazol, a blocker of the related enzyme PDE3, already relieves walking pain in the same patient population. A different approach to the same disease works without a drug: a meta-analysis of 68 studies on vascular cell transplantation found a near doubling of blood flow but could not link that improvement to whether the transplanted cells actually engrafted in the vessel. In that case the mechanism remained unknown; here it has been mapped down to the receptors and the switching protein.

VEGF is not a new discovery: the protein was purified and named in 1989, and it is now a drug target in cancer and age-related retinal disease, where therapies work by suppressing its activity rather than enhancing it.

The age-weakened vascular repair signal can be restored with a drug that already exists, without waiting for one to be developed from scratch.