Endothelial cell dysfunction in cardiac disease: driver or consequence?

Figures

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  FIGURE 1. Cardiac diseases and known associations with endothelial dysfunction. Blunted myocardial perfusion as assessed by coronary flow reserve (CFR) or flow-mediated dilation (FMD) reflects impaired vasomotor activity, a major sign of endothelial dysfunction. Structural changes to the microvasculature further compound the loss of myocardial blood flow, often leading to pro-fibrotic and pro-hypertrophic signaling in the diseased heart. Diminished nitric oxide (NO) bioavailability also promotes vascular smooth muscle cell proliferation, leading to thickening of the vascular wall. A number of heritable mutations are well-known drivers of hypertrophic cardiomyopathy (HCM), moreover, population-level genetic analysis has led to investigation of several variants that may be implicated in other conditions. Created with BioRender.com.

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  FIGURE 2. Paracrine mediators dysregulated in dysfunctional endothelium leading to altered cardiomyocyte phenotype. Loss of nitric oxide (NO) bioavailability is central to disruption of cardiomyocyte homeostasis, driving changes in cardiac growth, inflammation, and inotropy in addition to furthering autocrine dysfunction. Upregulation of vasoactive peptides such as endothelin-1 and angiotensin-II leads to further deterioration of vasomotor control in addition to mediating hypertrophic and fibrotic changes. Developmental factors such as neuregulin-1 influence postnatal cardiac growth and contractility, whereas decreased apelin-1 signaling similarly impairs endothelial-cardiomyocyte supporting functions. Colored boxes indicate signaling pathways directly implicated in each cardiomyocyte phenotypic change. Created with BioRender.com.

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  FIGURE 3. Initiating events leading to endothelial dysfunction. Circulating pro-inflammatory factors cause activation of intracellular effectors such as NLRP3 and NF-κB, which stimulate increased expression of adhesion molecules, loss of barrier function, and propagation of inflammatory signaling. Overabundance of cellular oxidative species leads to eNOS uncoupling and impaired NO bioavailability, in addition to suppressed anti-inflammatory regulation. Disturbed flow across the endothelial surface is transmitted by mechanosensitive elements leading to pro-inflammatory activation. All of the above initiators, in addition to TGF-ß signaling, may induce loss of endothelial identity and a shift towards a profibrotic, contractile phenotype (EndMT). Created with BioRender.com.

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  FIGURE 4. In vivo vs. in vitro systems for modeling endothelial dysfunction and complex cardiac disease. Animal models allow experimental induction of clinical symptoms that closely resemble those seen in cardiac conditions such as INOCA/ANOCA, HCM, and HFpEF. Resultant functional changes such as diminished coronary flow are also readily quantified in such models. In recent years, “multi-hit” models of heart disease have more precisely captured the influence of comorbidities typically present in human pathologies. Conversely, in vitro platforms permit modeling with human cells, and have already shown great utility in hiPSC-based modeling of genetic diseases. Extensive customizability of in vitro systems allows controlled interrogation of cell-cell signaling, spatial organization, and hemodynamic environments. Introduction of other cardiac cell types, such as endothelial cells, fibroblasts, neurons, and immune cells promises to further recapitulate native human pathophysiology. Created with BioRender.com.