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Accounting for capillaries
TAMPA, Fla.—Capillaries are part of the human blood vessel system which transports oxygen and nutrients around the body, and are the smallest vessels in that system; as noted by the Encyclopedia Britannica, “The capillary networks are the ultimate destination of arterial blood from the heart and are the starting point for flow of venous blood back to the heart.” While they don't get as much focus as the larger parts of the circulatory system, they play important roles in proper bodily function and their loss of function—or wholesale loss—has widespread effects. A study led by the University of South Florida Health (USF Health) explored what causes the loss of these tiny blood vessels and how to combat their degeneration. USF researchers worked alongside the laboratory of Dr. Courtney Griffin at the Oklahoma Medical Research Foundation, and their findings were published in Arteriosclerosis, Thrombosis, and Vascular Biology, an American Heart Association journal.
“Capillary regression (loss) is an underappreciated, yet profound, feature of many diseases, especially those affecting organs requiring a lot of oxygen to work properly,” said Dr. George E. Davis, a professor in the Department of Molecular Pharmacology and Physiology at the USF Health Morsani College of Medicine.
Indeed, as the authors note in the paper, “Capillary loss or rarefaction is observed in major human diseases including ischemia and infarction, hypertension, diabetes mellitus, malignant cancer, neurodegenerative diseases, and wound repair responses.”
According to a post by USF's Anne DeLotto Baier, the research team found that the proinflammatory mediators interlukin-1 beta (IL-1β), tumor necrosis factor alpha (TNFα) and thrombin are key drivers of capillary loss, both individually and when combined.
“Proinflammatory mediators are known to have a profound influence on the vasculature and cause increased vascular permeability, altered vascular morphogenic responses, leukocyte adhesion and transmigration, increased procoagulant activities, and increased platelet adhesion and aggregation,” the authors reported. “Key mediators include IL (interleukin)-1, TNF (tumor necrosis factor), and thrombin, as well as many other cytokines and small molecule mediators that regulate these processes in health and disease states. Many recent studies indicate the therapeutic benefits in humans of neutralizing antibodies or pharmacological antagonists directed to IL-1β, TNFα, and thrombin in key disease states including atherosclerosis, proinflammatory diseases (eg, arthritis, Crohn disease, and psoriasis), prothrombotic diseases (eg, deep venous thrombosis and pulmonary embolism), and malignant cancer.”
This work was enabled by the Davis laboratory's specialization in growing models of blood vessel networks, with the lab's website noting that it has developed “in-vitro methods under serum-free defined conditions and in 3D extracellular matrices” for the study of capillary formation. The researchers used this technology to culture endothelial cells, which line the inside of capillaries and other blood vessels, and pericytes, which surround “the outer surface of the endothelial-lined tubes,” as per DeLotto Baier's post. Macrophages were then introduced into the culture media to replicate the kind of tissue injury that would lead to capillary loss.
What they found was that IL-1β, TNFα and thrombin together trigger a “capillary regression signaling signature” that contributes to the loss of capillaries, as noted in DeLotto Baier's press piece. That signature is an opposite of previously identified pathways noted by Davis and colleagues as playing a role in the formation and growth of capillaries.
Thanks to existing drugs that already target the inflammatory culprits, the team pinpointed two drug combinations that can inhibit capillary loss. Anti-IL-1β and TNFα antibodies are administered to treat diseases such as rheumatoid arthritis, Crohn's disease and atherosclerosis, and thrombin inhibitors are on the market for patients diagnosed with conditions such as atrial fibrillation, pulmonary embolisms and/or deep vein thrombosis.
“These drugs are out there and they work. Our data suggests that, if combined, they may actually prevent vessel breakdown (earlier in the disease process) and improve outcomes,” Davis commented.
Specifically, the researchers identified a four-agent combination of drugs that “completely rescued the proregressive influence of IL-1β, TNFα, and the proregressive macrophage media,” which they named “FIST.” FIST is comprised of “forskolin and IBMX (3-Isobutyl-1-methylxanthine; to stimulate cyclic AMP levels), SB239063 (to inhibit p38 Map kinase), and tubacin (to inhibit the tubulin deacetylase HDAC6).” They also noted that when a fifth drug—SB415286, which inhibits GSK3β—is added, the resulting combination (FISTSB) “can protect better against the combination of IL-1β and TNFα and especially when thrombin is added with these cytokines.” Rather than simply halting the degeneration of capillaries, “the FIST or FISTSB drug combinations can rescue back to control or above control every proregressive factor or combination of factors that we have identified to date.”
There are still more questions to be answered about this process, however. As they continue to pursue this avenue of research, Davis and his lab intend to explore how capillary regression can lead to cell and tissue loss in conditions such as ischemic heart disease, sepsis and stroke.
Source: USF.edu post by Anne DeLotto Baier