Research News

Above: Endothelial cells are stained green in this immunofluorescence staining of an advanced atherosclerotic lesion in a preclinical model.

Cleveland Clinic has published an unprecedented look at how cells that line the main artery in our bodies contribute to sex-based differences in heart disease.

People who are assigned male or female at birth are diagnosed and treated for heart disease differently, based on overlapping but significantly different symptoms. Researchers investigating sex-based differences in heart failure typically look to hormones for an explanation, while this study examined the cells themselves, says Olga Cherepanova, PhD, assistant staff in Cardiovascular and Metabolic Sciences and corresponding author for the study. 

The findings, published in Arteriosclerosis, Thrombosis, and Vascular Biology, focus on aortic endothelial cells, which assist in oxygen exchange and blood flow. The research team found female endothelial cells show more of the characteristics that promote heart disease than their male counterparts. These characteristics are involved in inflammatory and immune responses. 

"This study is the first to our knowledge to provide a compelling characterization of both female and male endothelial aortic cells," Dr. Cherepanova says, noting young women often experience atypical heart attack symptoms. "Our approach highlighted the dire need to incorporate male and female models into each stage of heart disease research because these cells function and respond to treatment differently." 

Historically, most preclinical work and clinical trials have focused on people assigned male at birth. Because of this, there are still many unanswered questions about how heart disease develops and affects people assigned female at birth. For example, estrogen has been considered an athero- and cardio-protective factor prior to menopause, but further research did not justify postmenopausal hormone therapy to prevent cardiovascular disease.

The study examined sex-based differences during the development of atherosclerosis – when abnormal lesions called plaques form on the walls of blood vessels. These plaques affect blood flow and other blood vessel functions. In addition to differences at the cellular level, Dr. Cherepanova's team found females developed larger plaques in the aorta under the same conditions in preclinical models. Females also were more likely to develop problems with how blood vessels expand and constrict.

The differences were also consistent when researchers analyzed gene expression, a way to know what cellular functions are "turned on" or "off" based on the presence of RNA in the cells. Female cells showed higher gene activity related to inflammation, metabolism and blood vessel formation. 

Junchul Shin, PhD, the study's first author and a research associate in Dr. Cherepanova's lab, says these differences show endothelial function varies as a biological variable and critical function in vascular health. Further investigations into the underlying causes of these differences – particularly related to hormones and sex-chromosome genes – would help further this understanding and potential translation to patient care.

Dr. Cherepanova's team tapped experts from across Cleveland Clinic's Lerner Research Institute and across the country to confirm their new observations. These researchers also study endothelial cells and atherosclerosis. Collaborators include:

• LRI's Olga Stenina Adognravi, PhD, whose lab studies the mechanisms of diabetes and glucose control and the relationship to atherosclerotic lesions
• LRI's Tatiana Byzova, PhD, whose lab studies angiogenesis and blood vessel biology
• LRI's Eugene Podrez, PhD, whose lab studies how inflammation and oxidative stress contribute to heart disease
• Case Western Reserve University's Sanjay Rajagopalan, MD, who directs CWRU's Cardiovascular Research Center
• University of Arizona's Casey Romanoski, PhD, whose lab connects DNA variation and gene regulation and primarily focuses on endothelial cells