Dynamics of Endothelial Cell Diversity and Plasticity in Health and Disease

Abstract

Endothelial cells (ECs) are vital structural units of the cardiovascular system possessing two principal distinctive properties: heterogeneity and plasticity. Endothelial heterogeneity is defined by differences in tissue-specific endothelial phenotypes and their high predisposition to modification along the length of the vascular bed. This aspect of heterogeneity is closely associated with plasticity, the ability of ECs to adapt to environmental cues through the mobilization of genetic, molecular, and structural alterations. The specific endothelial cytoarchitectonics facilitate a quick structural cell reorganization and, furthermore, easy adaptation to the extrinsic and intrinsic environmental stimuli, known as the epigenetic landscape. ECs, as universally distributed and ubiquitous cells of the human body, play a role that extends far beyond their structural function in the cardiovascular system. They play a crucial role in terms of barrier function, cell-to-cell communication, and a myriad of physiological and pathologic processes. These include development, ontogenesis, disease initiation, and progression, as well as growth, regeneration, and repair. Despite substantial progress in the understanding of endothelial cell biology, the role of ECs in healthy conditions and pathologies remains a fascinating area of exploration. This review aims to summarize knowledge and concepts in endothelial biology. It focuses on the development and functional characteristics of endothelial cells in health and pathological conditions, with a particular emphasis on endothelial phenotypic and functional heterogeneity.

Keywords: BMP; EMT; EndMT; NOTCH; TGF; VGF; WNT; cancer; development; endothelial cells; endothelial regeneration; endothelial turnover; macrocirculation; microcirculation.

Figure 1

(A). Interaction and cross-talk between different pathways in endothelial development and function. Molecular signaling cross-talk: WNT/VEGF-A: in ECs, WNT-pathway is constitutively suppressed in ECS. WNT-ligand activates FRZ receptors through the inactivation of the destruction complex (APC-c-Cbl β-TrCP- β-catenin) and translocation of β-catenin to the nucleus with further activation of VEGF-A; VEGF/NOTCH demonstrates a synergistic effect. VGF, through the VEGFR2, increases expression of DLL4, leading to NOTCH activation. NOTCH receptors demonstrate synergism (VEGF 1, VECGF3) and antagonism (VEGF2) in VEGF expression; NOTCH/BMP activates expression of the inhibitory I-SMAD protein, leading to inhibition of BMP 2/6; NOTCH/TGF-β cross-talk is characterized by downstream of ALK receptors and depends on R-SMAD and Co-SMAD activation with the formation of SMAD/NICD complex of transcription (similar to β-catenin/NCID complex). As a result, the FGF-β-induced expression of NOTCH target genes (HEY/HES) leads to migrations of ECs; BMP/WNT/TGF-β demonstrate synergetic regulation and determine ligand production of each other; WNT/TGF-β cross-talk leads to synergetic regulation of the set of shared target genes in the nucleus via the Smad/Lef/β-catenin. NOTCH/WNT cross-talk is complex and involves several regulation levels: formation of β-catenin/NICD transcriptional complex (orange lines), the interplay between NOTCH receptors and β-catenin at the membrane (pink lines), NICD phosphorylation by GSK3b (blue lines), and inhibitory interaction between CSL and Disheveled (DVL) and inhibition of effector gene expression (green). (B) Schematic representation of the pathway signaling cross-talk in ECs: APC—adenomatous polyposis coli; BMP—bone morphogenetic proteins pathway; BMP ligands: BMP 2,4,5,6,7; BMPR—bone morphogenetic proteins receptor; b-TrCP (Fbxw1 or hsSlimb)—β-transducin repeat-containing protein; b-TrCP-p—phosphorylated b-TrCP; c-Cbl—casitas B lineage lymphoma protein with Ee ligase activity; c-Cbl-p—phosphorylated c-Cbl; Co-SMADS: SMAD 4; CSL-(CBF1, suppressor of hairless, Lag1)—transcription factor activating the genes downstream of the NOTCH pathway; HES 1,2—hairy and enhancer of split 1,2; HEY 1—hairy/enhancer of split related with YRPW motif protein 1; I-SMADS: SMADS 6, 7; NICD—NOTCH intracellular domain; R-SMADS: SMADS 1,2,3,5,8; TGF-β—transforming growth factor β; TGF-b ligands: TGF-b 1. 2,3; VEGF-A—vascular endothelial growth factor A; VEGFR—vascular endothelial growth factor receptors; WNT—wingless-related integration site.

Figure 2

Continuous ECs showing diversity in various organs: (A) medullary sinus of lymph node (SEM: surface scanning electron microscopy); (B) brain with tight junctions (TJ) of the blood–brain barrier (TEM: transmission electron microscopy); (C) ECs of arteries (SEM); (D) ECs of veins (SEM); (E) EC of capillary of dermis/skin (TEM). Kindly provided by emeritus professor P. Groscurth through https://e-learn.anatomy.uzh.ch/Anatomie/Anatomie.html.

Figure 3

Fenestrated ECs showing diversity in the organs: (A) ECs of kidney glomerulus (SEM); (B) ECs of kidney glomerulus (TEM); (C) adrenal gland capillary with fenestrated ECs and fenestral diaphragms (FD) (TEM); (D) ECs of the sinusoid of liver (SEM). (Kindly provided by emeritus professor P. Groscurth through https://elearn.anatomy.uzh.ch/Anatomie/Anatomie.html).

Figure 4

Schematic representations of different types of endothelium: (A) Schematic drawing of continuous endothelium; (B) schematic drawing of fenestrated endothelium (glomerular fenestrated endothelium (true fenestrated), with fenestrae ~60–100 nm in diameter), TJ (tight junctions), and AJ (adherens junctions); (C) schematic drawing of pseudo fenestrated endothelium with fenestral diaphragm (FD (fenestrae ~60–70 nm in diameter); and (D) schematic drawing of discontinuous sinusoid endothelium with GJs (gap junctions), TJs, and large pores ~100–200nm.