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.

Circulating Levels of Epirubicin Cause Endothelial Senescence While Compromising Metabolic Activity and Vascular Function

“…Importantly, cell senescence is associated with an inflammatory microenvironment ( Coppé et al, 2008 ; Kuilman et al, 2008 ; Wajapeyee et al, 2008 ), identified in epirubicin-treated hUVEC conditioned medium ( Figures 2C,D ). The effects of inflammation in vascular function are notably reciprocal, and associated with a myriad of chronic health conditions, such as diabetes, aging and neurodegeneration and multiple respiratory syndromes ( Augustin and Koh, 2017 ; Reiterer and Branco, 2020 ).…”

“…Human umbilical vein EC (hUVEC) were used to investigate effects on EC survival and function. Additionally, naïve (tumor-free) mice were treated with intravenous epirubicin to assess effects of treatment on lung vascular parameters, considering that lung disease and associated comorbidities are heavily associated with vascular dysfunction ( Reiterer and Branco, 2020 ), and this is also a common metastatic site. Primary microvascular EC (MVEC) were also isolated from lung tissue ( Reiterer et al, 2019 ) to investigate the effects of epirubicin on EC behavior following in vivo exposure.…”

Circulating levels of epirubicin cause endothelial senescence while compromising metabolic activity and vascular function

“…Importantly, cell senescence is associated with an inflammatory microenvironment (Coppé, Patil et al 2008, Kuilman, Michaloglou et al 2008, Wajapeyee, Serra et al 2008, identified in epirubicin-treated hUVEC conditioned medium (Figure 2C, D). The effects of inflammation in vascular function are notably reciprocal, and associated with a myriad of chronic health conditions, such as diabetes, ageing and neurodegeneration and multiple respiratory syndromes (Augustin andKoh 2017, Reiterer andBranco 2020).…”

Life after Cell Death—Survival and Survivorship Following Chemotherapy

“…EC form a continuous but very heterogeneous organ, with unique functional and metabolic profiles, which responds to stress and inflammation in an organ-specific manner [50]; this may actually underlie therapy-driven metastatic organotropism. Most studies investigating vascular damage in response to prolonged exposure to chemotherapy use HUVECs as their model, which does not address the impact on organ function in light of microvascular heterogeneity [51]. For example, expression of genes involved in substrate transport, ECM remodelling, barrier function and endothelial activation, are significantly altered following doxorubicin exposure [52], but their baseline expression varies significantly across the microvascular EC of the brain, lung and heart [50]-the first two are common metastatic organs for TNBC [53], and the cardiac microvascular EC perform essential roles in cardiac muscle function [54].…”

“…While microvascular cell plasticity ensures that metabolic demands are met at specific organs and in specific contexts [64], their adaptive responses to stress can involve structural, angiogenic, intercellular communication and metabolic changes likely to favour dissemination and proliferation of circulating tumour cells (CTC) [48,51,[65][66][67]. In turn, CTC have been shown to more efficiently evade cytotoxic treatments, as a result of enhanced DNA repair mechanisms [68].…”