Research News

A recent publication in Angiogenesis describes the role that stem cell protein Octamer-binding transcriptional factor 4, or OCT4, plays in angiogenesis, the process of generating new blood vessels. Angiogenesis is essential for healing wounds, repairing tissue, and transporting oxygen and nutrients throughout the body. The same process, though, can contribute to cancer, cardiovascular disease, and inflammatory and autoimmune diseases. 

The new study shows that OCT4 helps regulate blood vessel growth, but produces different results in males and females—including how quickly wounds heal. OCT4 is an important protein that helps certain cells stay like “blank slates,” meaning they can turn into almost any type of cell in the body. Until now, nothing was known about the role of this protein in sex differences in adults.

Chasing the “why” behind sex differences in blood vessels 

Olga Cherepanova, PhD, associate staff in Cleveland Clinic Research and corresponding author for the new article, has studied OCT4 for the past few years. She regularly collaborates with fellow researchers Tatiana Byzova, PhD, and Eugene Podrez, PhD. In a 2022 article published in Cardiovascular Research, the team identified OCT4’s role in endothelial cells—the thin, flat cells that line the inside of blood vessels and prevent toxic and dangerous substances from getting into the bloodstream. The OCT4 gene acts as a protector against the plaque buildup that characterizes atherosclerosis by maintaining healthy cellular metabolism and regulating cellular activities.

Further research from Dr. Cherepanova’s laboratory showed sex-based differences in the characteristics of aortic endothelial cells. Female endothelial cells, they found, show more of the characteristics that promote heart disease than males. 

“Our 2023 publication highlighted to the research community that females and males have different blood vessel cell characteristics, which was relatively new information and emphasized the need to incorporate models of both biological sexes into research,” says Dr. Cherepanova. “That finding wasn’t the endpoint for us, though. We wanted to look further and find out why.”

Learning more about OCT4’s role  

The new Angiogenesis study highlights the researchers’ finding that males and females differ in how their bodies respond in some conditions (both healthy and disease) that rely on the formation of new blood vessels. They focused on understanding the role of OCT4 in processes that do not involve atherosclerosis, the hardening and narrowing of arteries due to plaque buildup.

Loss of OCT4 activity in endothelial cells was associated with sex‑specific differences in angiogenesis and tissue response. In males, reduced OCT4 signaling correlated with more rapid wound healing, increased formation of new blood vessels, and quicker recovery of blood flow following vascular obstruction. Females, by contrast, exhibited delayed skin wound healing accompanied by accelerated melanoma tumor growth.

"These findings demonstrate that biological sex changes how blood vessels grow and repair themselves, which is important as we think of developing future treatments for cardiovascular disease and cancer," Dr. Cherepanova says. "Females tend to have higher baseline levels of inflammation in their bodies, which is perhaps why OCT4 is more of a 'helper' for them. Males, however, rely more on angiogenesis to heal, and deactivating it in our trials highlighted how much OCT4 impacted their blood vessel development."

The future of OCT4 research

The knowledge gained in this study about OCT4 could lead to new ways to speed up healing after injuries and surgeries, and to slow down cancer growth by targeting OCT4-dependent signals. In the future, scientists want to learn how to safely adjust OCT4 so it helps the body heal without causing problems like cancer or heart disease. They may also study how to personalize treatments based on known differences between males and females.