PATHOPHYSIOLOGICAL SIGNIFICANCE OF ENDOTHELIAL HETEROGENEITY

Highlights Acquisition and maintenance of organ-specific endothelial signatures depend on the flow- and matrix-derived biophysical stimuli, juxtracrine, paracrine and endocrine biochemical cues, and comorbid conditions. Being tailored to the organ-specific needs, capillary endothelial cells have significant heterogeneity and high molecular plasticity. Whilst endothelial heterogeneity in vivo is evident, molecular heterogeneity of arterial, venous, and microvascular endothelial cells in vitro and its pathophysiological significance still remain unclear. Abstract In this review, we consider molecular and pathophysiological heterogeneity of distinct endothelial cell (EC) lineages and organ-specific ECs. Recent single-cell sequencing studies showed a significant endothelial heterogeneity at physiological and pathological conditions and found that molecular heterogeneity of arterial, venous, and microvascular ECs is lower than in ECs of different organs, also showing higher heterogeneity of vascular as compared with lymphatic ECs. Acquisition and maintenance of organ-specific endothelial signatures depend on organ-specific biophysical setup (i.e., shear stress, cyclic loading, and extracellular matrix stiffness); 3) biochemical profile of circulating blood (including blood gas composition and molecular profile); 3) juxtacrine and paracrine molecular signals from adjacent cell populations and surrounding extracellular matrix; 4) concomitant pathological conditions within the organ such as inflammation, hypoxia, and fibrosis. Because of tailoring to the organ-specific needs, capillary endothelial cells have significant heterogeneity and molecular plasticity, exhibiting the highest adaptation potential in comparison with arterial and venous ECs. Whilst capillary ECs lack common molecular signatures, arterial and venous ECs have specific markers in the embryonic state (COUP-TFII transcription factor and ephrin type-B receptor 4 (EPHB4) in venous ECs; HEY1, HEY2, and HES1 transcription factors, gap junction proteins GJA4 и GJA5, semaphorin 3G, and ephrin B2 (EFNB2) in arterial ECs). Nevertheless, molecular heterogeneity of distinct EC specifications in vitro and its pathophysiological significance in the absence of confounding biophysical and biochemical factors remains obscure.