Targeting endothelial dysfunction and inflammation

https://doi.org/10.1016/j.yjmcc.2022.04.011Get rights and content

Highlights

  • Vascular endothelium controls vascular homeostasis by maintaining a healthy balance between EDRFs and EDCFs.

  • Endothelial dysfunction is featured by impaired endothelium-dependent relaxations and contractions.

  • The cardiovascular risk factors can increase the expression of BMP4-ROS-COX-2 cascade to release EDCFs.

  • Many drugs and agents potentially inhibit the expression and activity of inducers of COX-2 upregulation.

  • Deeper understanding of the molecular mechanism underlying endothelial dysfunction help develop new therapeutic drugs.

Abstract

Vascular endothelium maintains vascular homeostasis through liberating a spectrum of vasoactive molecules, both protective and harmful regulators of vascular tone, structural remodeling, inflammation and atherogenesis. An intricate balance between endothelium-derived relaxing factors (nitric oxide, prostacyclin and endothelium-derived hyperpolarizing factor) and endothelium-derived contracting factors (superoxide anion, endothelin-1 and constrictive prostaglandins) tightly regulates vascular function. Disruption of such balance signifies endothelial dysfunction, a critical contributor in aging and chronic cardiometabolic disorders, such as obesity, diabetes, hypertension, dyslipidemia and atherosclerotic vascular diseases. Among many proposed cellular and molecular mechanisms causing endothelial dysfunction, oxidative stress and inflammation are often the pivotal players and they are naturally considered as useful targets for intervention in patients with cardiovascular and metabolic diseases. In this article, we provide a recent update on the therapeutic values of pharmacological agents, such as cyclooxygenase-2 inhibitors, renin-angiotensin-system inhibitors, bone morphogenic protein 4 inhibitors, peroxisome proliferator-activated receptor δ agonists, and glucagon-like peptide 1-elevating drugs, and the physiological factors, particularly hemodynamic forces, that improve endothelial function by targeting endothelial oxidative stress and inflammation.

Section snippets

Regulation of endothelial function

Endothelial cells lining the lumen of blood vessels play critical roles in the regulation of vascular homeostasis. Both circulating vasoactive substances and blood flow-induced mechanical force are the natural stimuli to control the relative contribution of both endothelium-derived relaxing factors (EDRFs) and endothelium-derived contracting factors (EDCFs) in the regulation of peripheral vascular tone, resistance to blood flow and blood distribution. Under physiological settings, normal

Mediators of endothelium-dependent contractions

Several mediators are responsible for the regulation of endothelium-dependent contractions (EDCs). In healthy rodent arteries, EDC is usually masked by the predominant impact of EDRFs, especially nitric oxide (NO) on vascular tension, where NO is a free radical gas important to cell signaling functions, neurotransmission and endothelium-dependent relaxation. EDC was first reported probably in the aortas of spontaneously hypertensive rats [1]. Since ROS scavengers or inhibitors can suppress the

Inducers of COX-2 upregulation

Since treatment with inhibitors of both ROS and COX-2 equi-effectively suppresses EDC in arteries from hypertensive rats [10,21], sustained increase of oxidative stress in hypertension is likely to mediate the upregulation of COX-2 in endothelial cells. Indeed, the COX-2 expression is elevated in renal arteries from SHR and hypertensive patients while pharmacological inhibition of COX-2 rescued the impaired endothelial function in renal arteries from hypertensive patients and inhibited EDC in

Molecular mechanisms of COX-2 upregulation

The molecular mechanisms underlying COX-2 upregulation are comprehensive. COX-2 is normally expressed at a low level in healthy vasculatures, but its expression is highly inducible by the presence of growth factors and proinflammatory cytokines. It is now clear that COX-2 upregulation is closely related to increased oxidative stress in vascular endothelial cells under pathological situations (Fig. 1). Many oxidative stress inducers are involved in vascular dysfunction and atherogenesis; they

Clinical insights of COX-2 inhibition

Numerous preclinical studies have shown that increased oxidative stress in endothelial cells causes COX-2 upregulation to exacerbate endothelial dysfunction [34]. Although COX-2 is considered as a proinflammatory enzyme which interconnects multiple inflammatory processes during disease progression [35], conflicting clinical effects of COX-2 inhibition in the cardiovascular system have been reported [36]. For instance, prolonged exposure to the COX-2 inhibitor celecoxib in patients after

Restoration of endothelial function

All major cardiovascular risk factors such as high blood pressure, hyperglycemia, dyslipidemia, physical inactivity, estrogen deficiency or mental stress are known to increase vascular oxidative stress and cause endothelial dysfunction (Fig. 1), which ultimately leads to the development of atherosclerotic vascular diseases. Many drugs clinically used to treat patients with cardio-metabolic diseases are found to protect or preserve endothelial function through various mechanisms of action.

Hemodynamic forces, endothelial dysfunction, inflammation and atherogenesis

In addition to the forementioned exogenous agents, the endogenous physiological pattern of hemodynamic forces also modulates endothelial homeostasis. Vascular endothelial cells rapidly respond to changes in hemodynamic forces or blood flow patterns, and interact with circulating substances. The atherosclerotic plagues develop preferentially around arterial curvature and bifurcations where endothelial cells are constantly exposed to low-shear, disturbed or oscillatory blood flow. It is now well

Limitations and future perspectives

Although numerous preclinical studies suggest the beneficial effects of many pharmacological agents in lowering oxidative stress and inflammation in endothelial cells, a number of concerns need to be addressed to narrow the knowledge gap between preclinical observations and clinical implications. Importantly, pharmacological agents may elicit pleiotropic effects in various organs, potentially limiting the cardiovascular benefits or producing unexpected adverse effects. For instance, resveratrol

Conclusion

Endothelial dysfunction initiates a sequence of evolving pathological events in vascular endothelium eventually leading to the development of vascular complications in cardio-metabolic diseases. Mechanosensitive expression and activation of BMP4, a secretory peptide in endothelial cells can be considered as one of shared triggers for endothelial dysfunction in hypertension, obesity, and diabetes as several vaso-damaging factors such as oscillatory shear stress, elevated RAS activation, high

Author contributions

LW and YH conceptualized this work and prepared the manuscript. CKC, WL and YH revised the manuscript. MY and CKC collected required materials and made figures. KOL contributed constructive and valuable suggestions and revision.

Disclosure

None.

Acknowledgement

This work is supported by Natural Science Foundation of China (91939302, 81561128017, 81922077), Hong Kong Research Grants Council (SRFS2021-4S04, C4024-16W, 17118619, 14109618, 14164817, R4012-18, AoEM-707/18), Croucher Foundation Innovation Award and Health and Medical Research Fund (07181286, 08190776).

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