Researchers have discovered that the endothelial cells found in the veins of the lungs play a significant role in repairing blood vessels after lung injuries.
The pulmonary veins, which are responsible for transporting blood in the lungs, are crucial for lung function as well as for ensuring that tissues throughout the body receive adequate oxygen. When a person suffers lung damage due to illnesses such as influenza or COVID-19, it is essential to repair existing blood vessels and form new ones to fulfill oxygen needs. Unfortunately, research in this vital area is still quite limited.
Scientists from the University of Pennsylvania’s School of Veterinary Medicine and Perelman School of Medicine, along with researchers from the Children’s Hospital of Philadelphia (CHOP) and Vanderbilt University Medical Center, have been investigating how pulmonary venous endothelial cells (VECs) assist in the regeneration of blood vessels after lung injuries in adults. These endothelial cells line the interior of lung blood vessels and are important for regulating blood flow and the formation of new blood vessels, known as angiogenesis.
Their recent study reveals that these venous endothelial cells are capable of repairing damaged blood vessels in the lungs. After injuries caused by influenza, COVID-19, or high oxygen levels (hyperoxia), VECs multiply and expand into nearby capillary networks—tiny vessels that enable gas exchange—and contribute to the healing process.
Additionally, the research shows that VECs can change into capillary cells, indicating that this process is a reaction to lung injury rather than a normal part of lung development after birth. The results of their study have been published in Nature Cardiovascular Research.
“Many patients suffering from respiratory viruses, particularly those who are immunocompromised, can develop acute respiratory distress and may require intensive care,” explains Joanna Wong, the lead author and a Ph.D. student in Andrew E. Vaughan’s lab at Penn Vet. “Finding ways to enhance the regeneration of the lung’s vascular system could significantly improve modern medical practices and patient care.”
Vaughan, who is a co-senior author of the study alongside David B. Frank, a pediatric cardiologist and assistant professor at CHOP, notes that a high percentage of COVID-19 patients who died in intensive care did so due to acute respiratory distress syndrome, which has a mortality rate exceeding 30%. “Now that we’ve identified an important group of progenitor cells, we might manipulate these vein cells to enhance their repair capabilities,” Vaughan states, indicating a potential new therapeutic target.
The inspiration for this research originated from earlier studies conducted on zebrafish and mice. Vaughan points out that some studies indicated that in certain organs, a significant portion of capillary networks is formed through the expansion of veins. However, this had not been previously examined in the lungs.
Wong further highlights earlier work from Vaughan’s Lab before her arrival, where a postdoctoral fellow named Gan Zhao discovered that removing a specific vein-related transcription factor worsened lung injury while hindering the growth of endothelial cells.
Together, Vaughan and Wong propose that these studies led them and their associates to expect that the endothelial cells lining the lungs’ veins also play a part in repairing the capillary network following injury.
However, they faced one challenge: there were no tools available to isolate these specific cells and monitor them over time. Wong analyzed single-cell RNA sequencing data of pulmonary endothelial cells collected at different time points following an influenza injury. She identified an ideal marker, a gene named Slc6a2, which is unique to pulmonary veins. Collaborating with Frank, they developed a mouse model based on this gene.
“It was quite unexpected since Slc6a2 is also a norepinephrine transporter, traditionally associated with neurons, and we are still unclear why it is expressed in pulmonary veins,” she admits. Nevertheless, this fortuitous finding allowed her to trace the development of VECs in a genetically modified mouse model.
Looking ahead, Wong mentions that researchers aim to uncover the mechanisms that promote VEC growth and are also examining angiogenesis in different contexts, such as cancer.
Vaughan notes that the methods used in this research are applicable only after birth, but he is curious whether early embryonic veins contribute to forming blood vessels during lung development.
Joanna Wong is a doctoral candidate focusing on developmental, stem cell, and regenerative biology in the Cell & Molecular Biology Graduate Group at the University of Pennsylvania.
Andrew E. Vaughan is an associate professor of biomedical sciences at the University of Pennsylvania School of Veterinary Medicine and an assistant professor in the Institute for Regenerative Medicine at the Perelman School of Medicine.
David B. Frank is an assistant professor of Pediatrics in the Department of Pediatrics at Penn Medicine and serves as an attending physician at the Children’s Hospital of Philadelphia.
Other co-authors include Stephanie Adams-Tzivelekidis, Maria E. Gentile, Nicolas P. Holcomb, Sara Kass-Gergi, Xinyuan Li, Meryl Mendoza, Madeline Singh, and Gan Zhao from Penn Vet and Penn Medicine; Hongbo Wen, Prashant Chandrasekaran, and Sylvia N. Michki from Children’s Hospital of Philadelphia; Alan T. Tang from Penn Medicine; alongside Nicholas M. Negretti and Jennifer M.S. Sucre from Vanderbilt University Medical Center.
This study received support from the National Heart, Lung, and Blood Institute (grants R01HL164350 and R56HL167937); the Ayla Gunner Prushansky Fund; and a National Service Research Award Individual Predoctoral Fellowship.
