THE SECRET SUPREMACY OF SMALL BLOOD VESSELS, AN ENDURING PUZZLE OF THE CARDIOVASCULAR SYSTEM: RESEARCH GAPS AND OPPORTUNITIES



Zorina S. Gallis, Ph.D., National Heart, Lung, and Blood Institute, Bethesda, MD, USA

Small blood vessels are a critical component of the vascular system and essential for the maintenance and proper functioning of organs throughout the body. Their malfunction is a major contributor to local and systemic diseases. In spite of being part of the same system, small blood vessels have been studied traditionally within research and medical specialty silos aligning with specific organs and the diseases affecting them. The enduring challenge stems from the limited sharing and integration of the miscellaneous fundamental knowledge about diverse types of small blood vessel across body systems necessary to gain a cohesive understanding of how they individually and collectively function in health and disease. Emblematic for the “unity in diversity” of small vessels is the endothelium, the inner cell layer covering all blood vessels yet selectively mediating the local blood-tissue interactions. The endothelium can function as an only cellular layer of tiniest blood vessels that mediate most blood-tissue exchanges. Their complexity rests on anatomical and functional properties of specific endothelial cells, with extreme ability to respond to local environmental cues and functional demands. At the body level, endothelium functions as a complex mosaic layer, from creating completely tight barriers between blood and tissue to allowing translocation of entire cells. Even more puzzling are the mechanisms controlling local specificity of small blood vessel responses to systemic and long-range interactions, including mechanical, electro-chemical, and blood-borne signals. Lack of appreciation for small blood vessel complexity may be an important contributor to the bench-to the bedside gap in cardiovascular research. Advancement will require a systems approach for integrating information, from molecular to tissue to body level, informed by development of new sensitive biosensors and imaging. Understanding and harnessing the phenotypic and functional heterogeneity of small blood vessels may create new opportunities to specifically target tissues and organs for therapeutic interventions.