Endothelium emerges as central driver of disease
Functioning as a dynamic organ system, it regulates inflammation, blood flow, thrombosis and numerous disease processes throughout the body.
Scientific consensus is growing that the endothelium plays a more active role in human health than previously understood.
In fact, researchers are increasingly recognizing the vascular endothelium as one of the body's most influential organ systems and a key driver of cardiovascular and systemic disease, said Jason Kovacic, MD, PhD, FAHA, noting that it was once regarded as little more than a passive lining of blood vessels.
Kovacic explored that disconnect Friday during the session titled “The Thrombo-Inflammatory Axis: Bridging the Vessel Wall, Blood and Bedside.”
The endothelium helps regulate inflammation, blood flow, thrombosis and numerous disease processes throughout the body, Kovacic said during his presentation, “The Host: Endothelial Dysfunction as the Architect of Disease.”
“Data have now become compelling that the endothelium is a critical mediator of multiple diseases that include not only numerous vascular disease states, but systemic conditions and disease states as far ranging as diabetes, systemic inflammatory responses and obesity,” said Kovacic, a clinical professor of cardiology at both the Icahn School of Medicine at Mount Sinai in New York and the Victor Chang Cardiac Research Institute in Sydney, Australia. “Our understanding of the endothelium has evolved from that of a passive cell monolayer to a host and fundamental architect of disease.”
Kovacic’s presentation focused on the biological mechanisms driving endothelial dysfunction. Through lab research, his team has examined endothelial-to-mesenchymal transition (EndMT), a process in which endothelial cells change in ways that contribute to vascular disease development. Researchers have identified the signaling molecule SMAD3 as a critical regulator of this process, Kovacic said.
Experimental studies in cell-based and animal models showed that inhibiting SMAD3 can block EndMT and reduce neointima formation, a key factor in blood vessel narrowing after surgery. Researchers also reported improvements in vein graft patency in large-animal studies, findings that may pave the way for future therapeutic applications in vascular medicine. His team is now working to translate these discoveries into clinical practice.
“The endothelium is a complex organ system. There are multiple mechanistic pathways involved that reflect the diversity of vascular and systemic disease states that the endothelium orchestrates. Accordingly, the relevant mechanistic pathways involved are as diverse as the diseases themselves,” Kovacic said.
Kovacic also addressed the persistent challenge of residual cardiovascular risk. Although widely used lipid-lowering therapies, including statins and PCSK9 inhibitors, have significantly reduced cardiovascular events by lowering LDL cholesterol, Kovacic said many patients continue to experience heart attacks, strokes and other vascular complications despite optimal cholesterol management.
“This residual risk is partly driven by a thrombo-inflammatory loop where chronic, low-grade inflammatory and localized pro-thrombotic signaling conspire to transform a healthy, anti-thrombotic luminal surface into an active participant in atherothrombosis,” Kovacic said.
Beyond the cardiovascular implications, Kovacic called for a broader rethinking of endothelial biology. Comparing the evolving understanding of the endothelium to the scientific reassessment of what was formerly referred to as “junk DNA,” Kovacic said structures once dismissed as relatively unimportant are now understood to play essential biological roles. As the body’s largest organ system and one that interfaces with virtually every tissue, the endothelium is uniquely positioned to sense and integrate physiological signals that influence health and disease, he said.
“We now recognize ‘junk DNA’ as information-rich segments of noncoding DNA that are highly sophisticated and functional. Similarly, we have reached an inflection point in our understanding of the endothelium as both a host and an architect of disease,” Kovacic said. “Today, rather than just a vascular ‘inner tube’, the role of the endothelium as a fundamental orchestrator of various vascular and systemic conditions is increasingly apparent.”
Looking ahead, Kovacic said his team's recent research has explored endothelial health beyond Earth, suggesting that galactic cosmic rays, high-energy particles originating outside our solar system, appear to cause severe endothelial damage — although the Earth’s magnetic field and atmosphere provide some protection.
But Kovacic sounded a note of caution for agencies and companies attempting to establish human colonies on the moon or Mars: Experiments have shown that endothelial cells suffer profound injury when exposed to simulated space radiation comparable to what would be expected during extended missions beyond Earth’s magnetic field.
The Thrombo-Inflammatory Axis: Bridging the Vessel Wall, Blood and Bedside
3-4:15 p.m. | Friday, Nov. 6 | North Hall, Level 3
