MCG researchers uncover key pathway for new blood vessel growth

Researchers at the Medical College of Georgia at Augusta University have identified a previously unknown molecular pathway that helps new blood vessels grow and repair damaged tissue, a discovery that could lead to new treatments for cardiovascular and other vascular diseases.

The findings, published in Nature Communications, were led by Masuko Ushio-Fukai, PhD, professor of medicine in MCG’s Vascular Biology Center, and Tohru Fukai, MD, PhD, professor of pharmacology and toxicology in the Vascular Biology Center and co-principal investigator. Sheela Nagaracoti, PhD, a postdoctoral fellow in their laboratory, served as the study’s first author.

The study focuses on angiogenesis, the process by which new blood vessels form from existing vessels. Angiogenesis is essential for normal development, wound healing and tissue repair after injury. However, the body’s ability to grow new blood vessels is often impaired in people with diabetes, cardiovascular disease and advanced age.

The researchers discovered that a protein called Drp1, a key regulator of mitochondrial dynamics, serves as a critical molecular sensor that helps endothelial cells that line blood vessels respond to growth signals and generate the energy needed to build and repair vascular tissue. In doing so, Drp1 links growth-factor signaling with glycolysis, the energy-producing process that fuels blood vessel formation, even in low-oxygen environments.

“Healthy blood vessel growth requires close coordination between growth signals and cellular metabolism,” Ushio-Fukai said. “Our findings reveal a previously unrecognized mechanism that links those processes and helps drive angiogenesis.”

Drp1 was previously known for its role in controlling the shape and function of mitochondria, the structures inside cells responsible for producing energy. The new study found that Drp1 also acts as a molecular switch that helps endothelial cells translate growth-factor signals into the metabolic activity required for blood vessel formation and vascular repair.

The researchers also uncovered an important role for reactive oxygen species (ROS). While ROS are often associated with cellular damage, the study shows that controlled levels of these naturally occurring molecules produced during angiogenesis serve as important signaling messengers that help cells communicate.

In response to vascular endothelial growth factor (VEGF), one of the body’s most important drivers of blood vessel growth, ROS trigger a chemical change in Drp1 that activates a series of molecular events inside endothelial cells. When produced at the right place and time, these ROS activate Drp1 and help coordinate the complex cellular signaling required for vascular repair.

The team found that this signaling pathway boosts glycolysis, the process cells use to convert sugar into energy.

Endothelial cells are unusual because they obtain most of their energy through glycolysis, which does not require oxygen. Most other cell types rely primarily on oxidative phosphorylation, a more efficient process inside mitochondria that uses oxygen to generate energy. By favoring glycolysis, endothelial cells can continue functioning in low-oxygen environments and rapidly generate the energy needed to form new blood vessels during tissue repair.

The researchers found that Drp1 helps to activate this energy-producing pathway, ensuring endothelial cells have the fuel needed to migrate, proliferate, and organize into new blood vessels.

Using multiple mouse models, the team demonstrated that loss of Drp1 in endothelial cells significantly impaired blood vessel growth during development and reduced the body’s ability to restore blood flow after ischemic injury. Mice engineered with a mutation that prevented Drp1 from responding to ROS signals showed similar defects, confirming that this ROS-Drp1 signaling pathway is essential for normal blood vessel growth and repair.

The study identifies endothelial Drp1 as a previously unrecognized redox sensor, a protein that detects and responds to oxidation-related signals within cells. By coordinating growth-factor signaling, mitochondrial function and cellular metabolism, Drp1 serves as a key regulator of angiogenesis.

The discovery has important implications for conditions such as peripheral artery disease, ischemic heart disease and diabetes, where the body’s ability to form new blood vessels is often impaired and hinders recovery. By uncovering how Drp1 links cellular signaling, energy production and blood vessel growth, the researchers have identified a promising new therapeutic target for improving circulation and tissue repair.

“Our findings show that ROS are not simply harmful byproducts of cellular activity,” Ushio-Fukai said. “At the right amount, timing and place, they function as important signaling molecules that coordinate metabolism with tissue repair and blood vessel growth.”

By uncovering a new regulatory network connecting redox signaling, mitochondrial function and energy metabolism, the researchers say the work provides a foundation for future studies aimed at improving blood flow and tissue regeneration in patients with ischemic vascular diseases.

The research was supported by grants from the National Institutes of Health, including an NIH Program Project (P01) grant supporting investigations into the mechanisms underlying vascular disease.