Endothelial cells and organ function: applications and implications of understanding unique and reciprocal remodelling

Abstract

The microvasculature is a heterogeneous, dynamic and versatile component of the systemic circulation, with a unique ability to locally self-regulate and to respond to organ demand and environmental stimuli. Endothelial cells from different organs display considerable variation, but it is currently unclear to what extent functional properties of organ-specific endothelial cells are intrinsic, acquired and/or reprogrammable. Vascular function is a fundamental pillar of homeostasis, and dysfunction results in systemic consequences for the organism. Additionally, vascular failure can occur downstream of organ disease or environmental stress, often driving an exacerbation of symptoms and pathologies originally independent of the local circulation. The understanding of the molecular mechanisms underlying endothelial physiology and metabolism holds the promise to inform and improve diagnosis, prognosis and treatment options for a myriad of conditions as unrelated as cancer, neurodegeneration or pulmonary hypertension, and likely everything in between, if we consider that also treatments for such conditions are primarily distributed via the bloodstream. However, studying endothelial function has its challenges: the origin, isolation, culture conditions and preconditioning stimuli make this an extremely variable cell type to study and difficult to source. Animal models exist but are neither trivial to generate, nor necessarily adequately translatable to human disease. In this article, we aim to illustrate the breadth of microvascular functions in different environments, highlighting current and pioneering studies that have advanced our insight into the importance of the integrity of this tissue, as well as the limitations posed by its heterogeneity and plasticity.

Keywords: endothelial cell; metabolic reprogramming; microvasculature; organ-specific; tissue remodelling.

Figure 1

Overview of biological, chemical and physical influences on EC behaviour. Endothelial cells in capillary networks are exposed to tissue‐specific cues, which include signals from resident parenchymal and other stromal cells, the composition and stiffness of the ECM and the metabolic activity of the organ at any given time, which in turn affects the metabolite and gas composition, and extracellular pH. From the luminal side, EC perceive and respond to compounds and cells transported in circulation, such as nutrient status, circulating cells and oxygen levels (systemic influences); tissue‐specific influences include temperature and shear stress, which is altered as a function of vessel diameter, flow and branching; additionally, resident cells and metabolic, physiological and pathological status of specific organs in specific circumstances will provide the endothelium cues with very localized (tissue‐specific) relevance, but which can, too, provide systemic signals (e.g. angiocrine/endocrine). The activation status of the EC dictates its permeability, angiogenic potential, surface receptors and transporters, secretory profile and metabolism, and thus organ function.

Figure 2

Summary of local and systemic effects of specific EC parameters. Endothelial cells possess diverse combinations in surface receptors and transporters, as well as diffusible secretory compounds, which include growth factors (such as VEGF) and metabolites, which will be determined by intrinsic endothelial properties and tissue microenvironment/substrate availability; receptors, transporters and signalling molecules such as reactive oxygen species (ROS) or nitric oxide (NO), downstream of endothelial or inducible nitric oxide synthases (NOS), are also variables contributing to EC heterogeneity and plasticity. All these parameters are specific to individual capillary networks, but oscillate, in a more or less transient fashion, in response to local and systemic pressures. These alterations in endothelial behaviour, signalling and metabolic activity subsequently modulate local tissue microenvironment as well as systemic circulation patterns.