Heterogeneity and emergent behaviour in the vascular endothelium

Abstract

The endothelium is the single layer of cells lining all blood vessels, and it is a remarkable cardiovascular control centre. Each endothelial cell has only a small number (on average six) of interconnected neighbours. Yet this arrangement produces a large repertoire of behaviours, capable of controlling numerous cardiovascular functions in a flexible and dynamic way. The endothelium regulates the delivery of nutrients and removal of waste by regulating blood flow and vascular permeability. The endothelium regulates blood clotting, responses to infection and inflammation, the formation of new blood vessels, and remodelling of the blood vessel wall. To carry out these roles, the endothelium autonomously interprets a complex environment crammed with signals from hormones, neurotransmitters, pericytes, smooth muscle cells, various blood cells, viral or bacterial infection and proinflammatory cytokines. It is generally assumed that the endothelium responds to these instructions with coordinated responses in a homogeneous population of endothelial cells. Here, we highlight evidence that shows that neighbouring endothelial cells are highly heterogeneous and display different sensitivities to various activators. Cells with various sensitivities process different extracellular signals into distinct streams of information in parallel, like a vast switchboard. Communication occurs among cells and new ‘emergent’ signals are generated that are non-linear composites of the inputs. Emergent signals cannot be predicted or deduced from the properties of individual cells. Heterogeneity and emergent behaviour bestow capabilities on the endothelial collective that far exceed those of individual cells. The implications of heterogeneity and emergent behaviour for understanding vascular disease and drug discovery are discussed.

Endothelial TRPV4 channels modulate vascular tone by Ca2+‐induced Ca2+ release at inositol 1,4,5‐trisphosphate receptors

“…The response to activation of TRPV4 channels was also heterogeneous among cells. Some cells were highly responsive, while other cells responded weakly or not at all (see also Aird, 2012;Huang, Chu, Chen, & Jen, 2000;Lee et al, 2018;Marie & Beny, 2002; McCarron, Lee, & Wilson, 2017;McCarron et al, 2019;. We developed methods to automatically extract and separate the slow global increases and propagating Ca 2+ waves occurring in each endothelial cell.…”

Redox Signaling and Regional Heterogeneity of Endothelial Dysfunction in db/db Mice

“…The high morbidity and mortality rates in diabetic patients are largely due to cardiovascular complications [ 1 ]. Endothelial dysfunction is a key factor in diabetic vascular complications [ 2 , 3 ], as the endothelium regulates most aspects of vascular homeostasis including blood flow, blood clotting, angiogenesis, and inflammatory response [ 4 ]. Endothelium-dependent vasodilatation is an independent predictor of cardiovascular events and death in diabetic patients [ 5 , 6 , 7 ].…”

Disrupted Endothelial Cell Heterogeneity and Network Organization Impairs Vascular Function in Prediabetic Obesity

“…This structural architecture is unaltered by obesity. However, recent application of network theory to endothelial cell populations has started to uncover how rich functionality emerges from these structural connections and how network connectivity permits multiple physiological processes to be controlled [30][31][32][33] . Observing agonist-mediated endothelial Ca 2+ activity at the population level reveals spatial modules, or clusters of sensory cells, that detect activators and recruit agonist-insensitive cells to drive network activity.…”

“…In some tissues, heterogeneous cell populations may organize into spatial domains with coherent gene expression 64 , and it is thought that such multicellular groups form microcircuits, the building blocks of information processing. Clustering of endothelial cells permits the distribution of activities across space, i.e., different functional units can perform different processes simultaneously [30][31][32] . Such parallel processing requires cells that are responding to one stimulus to be resilient to interference from neighboring cells and this is facilitated by the organization of cells into clusters.…”

“…Distinct clusters of cells are tuned to detect specific activators, and different clusters detect different stimuli. This arrangement allows the endothelium to detect and process multiple stimuli in parallel and to generate stimulusspecific responses [30][31][32][33] . These findings, together with studies that describe molecular [34][35][36][37][38][39][40][41] and functional heterogeneity 40,42 in endothelial cells across vascular beds, and within single vessel segments, raise the possibility that dysfunctional vascular responses could arise from altered endothelial cell heterogeneity and disrupted network dynamics.…”