Louis Heiser & Robert Ackland
Bioengineers say they’ve found a way to accurately predict blood vessel growth, and this finding has implications for cancers and other diseases.
The team discovered that tiny blood vessels grow better in the lab if the tissue surrounding them is less dense.
And this discovery allowed them to create a computer simulation that can accurately predict such growth.
“Better understanding of the processes that regulate the growth of blood vessels puts us in a position, ultimately, to develop new treatments for diseases related to blood vessel growth,” said study author Jeff Weiss, PhD, of the University of Utah in Salt Lake City.
Dr Weiss and his colleagues described their research in PLOS ONE.
Like some previous studies, the group’s research showed that capillaries grow, branch, and interconnect best when the density of the surrounding tissue, the extracellular matrix, is lower rather than higher. But unlike earlier research, Dr Weiss and his colleagues used pieces of real blood vessels from rats (rather than single cells).
Earlier work also focused on how the extracellular matrix, made mostly of collagen, sends chemical signals to promote capillary growth. The current study focused more on how the collagen’s mechanical or physical properties—specifically, the density or stiffness of the matrix—affect blood vessel growth.
Both the lab experiments and computer simulations showed that the denser or stiffer this collagen matrix, the more difficult it is for blood vessels to form a network necessary to supply blood to living tissue.
Growing blood vessels
To grow a network of blood vessels, the researchers extracted blood vessel fragments from the fat tissues of rats and suspended them in liquid. This extract contained 35,000 of those blood-vessel fragments per mL of solution.
The blood vessel fragments were grown in plastic plates with tiny mold-like wells filled with gel-like collagen as the extracellular matrix. The team cultured the fragments for 6 days with 3 densities of collagen: 2 mg, 3 mg, and 4 mg of collagen per mL of solution.
Vessels in the lower-density collagen grew and branched more, had fewer dead ends, and interconnected with each other better than the vessels growing in the higher-density collagen. These blood vessel networks mirrored those found in living mammals.
Simulating growth
The vessels grown in the lab provided data on total length of the vessels, the degree to which they connected into a network of vessels, and the number of vessels branches and dead ends.
And these data allowed the researchers to program a 3-D computer simulation that accurately predicted blood vessel network formation based on collagen matrix density.
“Now, we can answer all sorts of ‘what if’ questions about the geometry of these tissues, their shape, boundaries, initial densities, and mechanical properties,” Dr Weiss said. “We can use the computer to predict the influence that these factors have in the layout of a vascular network structure.”
The 3-D computer simulation also enabled the researchers to “conduct” experiments that couldn’t be done in the lab. One simulation showed blood vessels grow easily from denser toward less-dense collagen, but not the other way around.
A second simulation showed that vessels grew in collagen, except where a dense piece of collagen was placed in the center of less-dense collagen.
The third simulation showed that when researchers simulated 2 bands of less-dense collagen surrounded by bands of stiffer collagen, the nerve vessels grew along the bands of lower density.
Applications for cancer, other diseases
The researchers said these findings could ultimately be applied to aid the development of treatments for patients with cancer or diabetes, as well as patients who have had a heart attack and those who require tissue implants.
By better understanding the role that density of surrounding tissue plays in vessel formation, bioengineers could prepare “prevascularized” implantable tissues already equipped with blood vessels that match a patient’s blood vessel structure.
Prevascularized tissues might also help diabetes patients suffering from wounds that heal slowly—if at all—due to impaired blood microcirculation. Implanted skin grafts with their own blood vessels could stimulate blood flow to promote healing of diabetic ulcers.
Dr Weiss said he envisions prevascularized patches rehabilitating heart muscle that is damaged when a heart attack cuts off part of the heart’s oxygen supply, turning some of the heart into stiff scar tissue. A tissue patch implanted on the scar tissue could encourage blood vessel regrowth to repair the damaged, oxygen-deprived heart muscle.
As for cancer metastasis, most tumors begin as dense, blood-free masses. To grow and spread, the tumor tricks the body into fueling it with oxygenated blood vessels.
“The vessels grow in and then provide a pathway for the tumor to spread,” Dr Weiss noted. “This research will help us understand the physical parameters that control whether blood vessels reach the tumor.”
