The laboratory of Dr. George Davis grows three-dimensional “blood vessel networks in a dish” under defined, serum-free conditions
Capillaries are our smallest, yet most abundant, blood vessels.
With walls barely as thick as a single red blood cell, they form exquisitely branching networks, spanning a total surface area of 1,000 square miles. Connecting with arteries and veins, capillaries exchange oxygen, nutrients and waste between the bloodstream and tissues throughout the body.
The laboratory of USF Health Morsani College of Medicine vascular cell biologist George Davis, MD, PhD, studies the basic biology of how capillaries form and stabilize and, more recently, what happens when these critical regulators of normal tissue function break down.
Healthy communication, or molecular signaling, inside and outside capillaries appears to play a critical role in promoting healthy tissues such as the heart, lungs and liver. Conversely, many diseases arise from abnormalities in blood vessels that fail to communicate properly with tissues, especially those requiring a lot of oxygen to work properly.
“I believe the root cause of many patient treatment failures is a lack of understanding of the underlying basis of disease,” said Dr. Davis, professor in the Department of Molecular Pharmacology and Physiology and member of the college’s USF Health Heart Institute. “My philosophy is that understanding the fundamental biology of capillaries in their normal state will lead to answers about what goes wrong in diseases,” including coronary artery disease, stroke, diabetes, and malignant cancers.
“If blood vessel formation is altered or begins to break down, we should be able to find a way to pharmacologically fix that.”
George E. Davis, MD, PhD, professor of molecular physiology and pharmacology, is a member of the USF Health Heart Institute.
Growing blood vessel networks “in a dish”
Dr. Davis joined USF Health in June 2018 from the University of Missouri-Columbia School of Medicine, where he was an investigator at the Dalton Cardiovascular Research Center. “What really attracted me to USF Health was having the opportunity to be part of a new heart institute being built around world-class research that interfaces with clinicians and biomedical engineering,” he said.
To delve into the complexity of capillary formation, Dr. Davis grows three-dimensional “blood vessel networks in dish” under serum-free, defined conditions to reduce variability. “The (cell culture) system we’ve developed over the years is really quite powerful, because it allows us to study molecular signaling — but also helps us in trying to understand what genes are regulated when vessels form,” he said.
His in vitro research primarily centers on two types of human cells – endothelial cells, which line the inner surface of capillaries, and pericytes, cells recruited to the outer surface of developing capillaries to help fortify the endothelial-lined tubes. He investigates the molecular “cross-talk” between these cells that controls how capillary networks arise and mature to support adjacent tissues.
Dr. Davis’ laboratory is known for discovering the combination of five growth factors (SCF, IL-3, SDF-1α, FGF-2 and insulin) needed to create viable human capillary networks in culture. Vascular endothelial growth factor (VEGF), considered to be a primary driver of blood vessel formation, surprisingly was not in mix; it did not directly stimulate the assembly of capillary networks.
Biological scientist Gretchen Koller works in Dr. Daviss laboratory.
Healthy capillaries as “disease suppressors”
His group defined at least two steps in capillary formation, validated by experiments. First, upstream priming by VEGF “wakes up” the capillary cells to respond to the five growth factors required for vessel assembly. Second, this now activated group of downstream factors promotes capillary tube formation and branching.
The Davis laboratory also recently proposed that healthy capillaries within tissues may be “disease suppressors,” since communication between endothelial cell-and pericyte-derived growth factors can inhibit basic disease mechanisms. These underlying pathological mechanisms include blood-clotting (thrombosis), inflammation, excessive fibrous connective tissue (fibrosis), inadequate blood supply (ischemia), and transformation of normal cells into cancer cells (carcinogenesis).
For example, Dr. Davis said, dysfunctional capillaries are a hallmark of diabetes — particularly for a complication known as diabetic retinopathy where pericytes drop off the tiny blood vessels in light-sensitive tissue at the back of the eye. This loss of pericytes, coupled with capillary breakdown leading to bleeding events, can lead to vision loss.
Even as they continue to uncover fundamental details about how capillary networks normally take shape, Dr. Davis’ team has reached a point where they can start applying what they’ve learned to attack, possibly even prevent, diseases.
“We want to take a model of capillary formation and create a diabetic-type state to see if we can mimic any of the changes in pericytes and the associated vessels observed in diabetes,” he said.
Endothelial cell-lined tubes (red) with associated pericytes (green). Both cell types co-assemble to create the capillary networks vital to the health of tissues throughout the body.
Applications for tissue regeneration
Besides helping identify potential treatments to repair dysfunctional capillaries or to promote their disease suppression capacities, the research may have applications for tissue regeneration. Engineering functional tissue to repair or replace a damaged heart, lung, kidney or other organs requires robust capillary networks.
“The biggest problem in creating these tissue engineered constructs has been a failure in the vasculature,” Dr. Davis said. “It’s critical to understand specifically what makes capillaries form and stabilize to sustain healthy tissue, so (when the construct does not work) it’s possible the growth factors added may not be the right ones.
“We’re working to figure out, in our defined system, which growth factors do what, and when they act.”
And the USF Health work in angiogenesis, the growth of new blood vessels, can provide insight into the control of tumor cell migration and invasion into distant tissues (metastasis). “If we can better understand the nuts and bolts of how to make a capillary network, we’ll gain a better sense of what makes the tumor microenvironment so abnormal,” Dr. Davis said.
Dr. Davis earned dual MD and PhD degrees from the University of California, San Diego, in 1986, and completed a medical staff fellowship (anatomical pathology residency) at the National Cancer Institute’s Laboratory of Pathology in Bethesda, MD.
Biological scientist Kalia Aguera
Dr. Davis’ research has been continuously funded by the National Institutes of Health (NIH) for more than 20 years. Working with a UT Southwestern colleague specializing in mouse genetic models of blood vessel development, he is co-principal investigator for a four-year, $1 million grant from the NIH’s National Health, Lung and Blood Institute. The project focuses on the role of VEGF-dependent signaling molecules in controlling downstream growth factors that prompt blood vessel formation.
Dr. Davis was among a group of scientists world-wide to develop the first consensus guidelines for use and interpretation of angiogenesis assays, published last year in the journal Angiogenesis. He has authored more than 140 peer-reviewed publications, and served as a member and chair of the NIH Cardiovascular Differentiation and Development Study Section.
Some things you may not know about Dr. Davis
- Drafted as an outfielder by a well-known baseball scout, he played after high school in a San Francisco Giants minor league team for a year before entering college. His perspective as a physician-scientist was shaped by intense determination that enabled him to excel at a team sport, and early medical training that included learning about a broad range of diseases and treating patients. “In science,” Dr. Davis said, “it’s critical to focus on the details, but you also need to understand the overall playing field, the big picture.”
- Davis and his wife Nancy have four grown children: a daughter, age 22, and three sons, ages 24 to 37.
-Photos by Allison Long, USF Health Communications and Marketing; Microscopic image of capillary co-assembly courtesy of George Davis laboratory
