Targeting endothelial dysfunction and inflammation
Graphical abstract
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).
References (102)
- et al.
Prostaglandins in action indispensable roles of cyclooxygenase-1 and -2 in endothelium-dependent contractions
Adv. Pharmacol.
(2010) - et al.
Endothelial cell transient receptor potential channel C5 (TRPC5) is essential for endothelium-dependent contraction in mouse carotid arteries
Biochem. Pharmacol.
(2019) - et al.
Blocking endothelial TRPV4-Nox2 interaction helps reduce ROS production and inflammation, and improves vascular function in obese mice
J. Mol. Cell. Cardiol.
(2021) - et al.
Cyclooxygenase-2-dependent oxidative stress mediates palmitate-induced impairment of endothelium-dependent relaxations in mouse arteries
Biochem. Pharmacol.
(2014) - et al.
Chronic cyclooxygenase-2 inhibition prevents the worsening of hypertension and endothelial dysfunction induced by ouabain in resistance arteries of spontaneously hypertensive rats
Vasc. Pharmacol.
(2021) - et al.
Calcitriol restores renovascular function in estrogen-deficient rats through downregulation of cyclooxygenase-2 and the thromboxane-prostanoid receptor
Kidney Int.
(2013) - et al.
Bone morphogenic protein-4 induces endothelial cell apoptosis through oxidative stress-dependent p38MAPK and JNK pathway
J. Mol. Cell. Cardiol.
(2012) - et al.
New horizons in the roles and associations of COX-2 and novel natural inhibitors in cardiovascular diseases
Mol. Med.
(2021) - et al.
Cardiovascular and bleeding risks associated with nonsteroidal anti-inflammatory drugs after myocardial infarction
J. Am. Coll. Cardiol.
(2020) - et al.
Endothelial contribution to COVID-19: an update on mechanisms and therapeutic implications
J. Mol. Cell. Cardiol.
(2022)
Bone morphogenic protein-4-induced oxidant signaling via protein carbonylation for endothelial dysfunction
Free Radic. Biol. Med.
Procyanidin B2 mitigates endothelial endoplasmic reticulum stress through a PPARδ-dependent mechanism
Redox Biol.
Resveratrol ameliorates endothelial dysfunction in diabetic and obese mice through sirtuin 1 and peroxisome proliferator-activated receptor δ
Pharmacol. Res.
Exendin-4 has an anti-hypertensive effect in salt-sensitive mice model
Biochem. Biophys. Res. Commun.
Hippo signaling: key emerging pathway in cellular and whole-body metabolism
Trends Endocrinol. Metab.
Revisiting pharmacology of oxidative stress and endothelial dysfunction in cardiovsacular disease: evidence for redox-based therapies
Free Radic. Biol. Med.
Endothelium-dependent contractions to acetylcholine in the aorta of the spontaneously hypertensive rat
Hypertension.
Oxygen-derived free radicals mediate endothelium-dependent contractions to acetylcholine in aortas from spontaneously hypertensive rats
Br. J. Pharmacol.
Endothelium-dependent contractions in SHR: a tale of prostanoid TP and IP receptors
Br. J. Pharmacol.
Cyclooxygenase-2-derived prostaglandin F2alpha mediates endothelium-dependent contractions in the aortae of hamsters with increased impact during aging
Circ. Res.
Vasoconstrictor prostanoids
Pflugers Arch.
Endothelium-mediated control of vascular tone: COX-1 and COX-2 products
Br. J. Pharmacol.
In SHR aorta, calcium ionophore A-23187 releases prostacyclin and thromboxane A2 as endothelium-derived contracting factors
Am. J. Physiol. Heart Circ. Physiol.
The calcium ionophore A23187 induces endothelium-dependent contractions in femoral arteries from rats with streptozotocin-induced diabetes
Br. J. Pharmacol.
Oxidative stress-dependent cyclooxygenase-2-derived prostaglandin f(2α) impairs endothelial function in renovascular hypertensive rats
Antioxid. Redox Signal.
Selective COX-2 inhibition improves endothelial function in coronary artery disease
Circulation
Short- and long-term COX-2 inhibition reverses endothelial dysfunction in patients with hypertension
Hypertension.
TRPV4 (transient receptor potential Vanilloid 4) mediates endothelium-dependent contractions in the aortas of hypertensive mice
Hypertension.
Endothelial TRPV4-eNOS coupling as a vital therapy target for treatment of hypertension
Br. J. Pharmacol.
Omega-3 fatty acids improve flow-induced vasodilation by enhancing TRPV4 in arteries from diet-induced obese mice
Cardiovasc. Res.
COMP (cartilage oligomeric matrix protein), a novel PIEZO1 regulator that controls blood pressure
Hypertension.
TRPV4, TRPC1, and TRPP2 assemble to form a flow-sensitive heteromeric channel
FASEB J.
Calcium and reactive oxygen species increase in endothelial cells in response to releasers of endothelium-derived contracting factor
Br. J. Pharmacol.
Bone morphogenic protein-4 impairs endothelial function through oxidative stress-dependent cyclooxygenase-2 upregulation: implications on hypertension
Circ. Res.
Inhibition of miR-200c restores endothelial function in diabetic mice through suppression of COX-2
Diabetes.
Endothelial dysfunction in small arteries of essential hypertensive patients: role of cyclooxygenase-2 in oxidative stress generation
Hypertension.
Regulators and effectors of bone morphogenetic protein signalling in the cardiovascular system
J. Physiol.
Pivotal role of protein kinase Cdelta in angiotensin II-induced endothelial cyclooxygenase-2 expression: a link to vascular inflammation
Arterioscler. Thromb. Vasc. Biol.
Regulation of YAP by mammalian target of rapamycin complex 1 in endothelial cells controls blood pressure through COX-2/mPGES-1/PGE 2 Cascade
Hypertension.
Flow-dependent YAP/TAZ activities regulate endothelial phenotypes and atherosclerosis
Proc. Natl. Acad. Sci. U. S. A.
Integrin-YAP/TAZ-JNK cascade mediates atheroprotective effect of unidirectional shear flow
Nature.
Endothelial TFEB (transcription factor EB) restrains IKK (IκB kinase)-p65 pathway to attenuate vascular inflammation in diabetic db/db mice
Arterioscler. Thromb. Vasc. Biol.
Interplay between oxidative stress, cyclooxygenases, and prostanoids in cardiovascular diseases
Antioxid. Redox Signal.
Cyclooxygenase-2 (COX-2) inhibitors: future therapeutic strategies for epilepsy management
J. Neuroinflammation
Association between nonsteroidal anti-inflammatory drug use and major adverse cardiovascular events in patients with end-stage renal disease: a population-based cohort study
J. Nephrol.
Cyclo-oxygenase (COX) inhibitors and cardiovascular risk: are non-steroidal anti-inflammatory drugs really anti-inflammatory?
Int. J. Mol. Sci.
Cyclooxygenase-2 selectively controls renal blood flow through a novel PPARβ/δ-dependent vasodilator pathway
Hypertension.
Renal medullary interstitial COX-2 (Cyclooxygenase-2) is essential in preventing salt-sensitive hypertension and maintaining renal inner medulla/papilla structural integrity
Hypertension.
Inhibition of cyclooxygenase-2 in hematopoietic cells results in salt-sensitive hypertension
J. Clin. Invest.
Angiotensin II type 1 receptor-dependent oxidative stress mediates endothelial dysfunction in type 2 diabetic mice
Antioxid. Redox Signal.
Cited by (37)
Nitric oxide: A potential etiological agent for vaso-occlusive crises in sickle cell disease
2024, Nitric Oxide - Biology and ChemistryThe peripheral corticotropin releasing factor family's role in vasculitis
2024, Vascular PharmacologySelection of goat β-casein derived ACE-inhibitory peptide SQPK and insights into its effect and regulatory mechanism on the function of endothelial cells
2023, International Journal of Biological MacromoleculesTargeting endothelial cells with golden spice curcumin: A promising therapy for cardiometabolic multimorbidity
2023, Pharmacological ResearchNeurovascular glial unit: A target of phytotherapy for cognitive impairments
2023, Phytomedicine