Immune and Metabolic Mechanisms of Endothelial Dysfunction

Abstract

Endothelial dysfunction is a strong prognostic factor in predicting the development of cardiovascular diseases. Dysfunctional endothelium loses its homeostatic ability to regulate vascular tone and prevent overactivation of inflammation, leading to vascular dysfunction. These functions are critical for vascular homeostasis and arterial pressure control, the disruption of which may lead to hypertension. Hypertension itself can also cause endothelial dysfunction, as endothelial cells are susceptible to haemodynamic changes. Although it is unclear which of those factors appear first, they create a vicious circle further damaging multiple organs, including the heart and vessels. There are also sex-specific differences in homeostatic functions of the endothelium regarding vessel tone regulation, which may contribute to differences in arterial blood pressure between men and women. Even more importantly, there are sex-differences in the development of endothelial dysfunction and vessel remodelling. Hence, an understanding of the mechanisms of endothelial dysfunction and its contribution to pathological vascular remodelling during hypertension is of critical importance. This review addresses immunological and metabolic aspects in mechanisms of endothelial dysfunction and the resulting mechanisms in vascular remodelling with respect to arterial hypertension, including the potential role of sex-specific differences.

Keywords: endothelial dysfunction; endothelium; hypertension; inflammation; metabolism; sex-differences; vessel remodelling.

Figure 1

Vasoactive factors produced by endothelial cells and the contribution of the endothelium in the conversion of ANGI to ANGII and substrate transport related to the endothelium. Created with Biorender (Toronto, Canada).

Figure 2

Mechanisms of endothelial dysfunction and contribution of dysfunctional endothelium to vessel remodelling.

Figure 3

Schematic representation of inflammatory imbalance and effectors mediating inflammation-dependent endothelial dysfunction.

Figure 4

Possible experimental targets modulating inflammation and adverse effects of metabolic stress which may protect from endothelial dysfunction.

Figure 5

Cellular mechanisms mediating endothelial dysfunction during metabolic stress.

Figure 6

Oestrogen acts via its receptors and maintains a balanced production of vasoactive peptides in favour of relaxing factors. Oestrogen acts partly directly but also via the expression of β₁- and β₃-adrenoceptors, which in turn activate eNOS (shown in rat model). The expression of more ACE2 on female endothelial cells allows it to effectively metabolise ANGII to ANG 1-7 and activate eNOS via MasR and AT2R, which are also expressed in female endothelial cells.