Research Progress and Molecular Mechanisms of Endothelial Cells Inflammation in Vascular-Related Diseases

Figures & data

Table 1 Endothelial Inflammation in Atherosclerosis

Ref.	Drug/Targets	Models (Cells or Animals)	Mechanisms of Protection	Diseases	Pathways
[44]	KLF14	IL-1β and TNF-α-induced HCAECs, HUVECs, THP-1 cells, Klf14 KO mice	Inflammation	Atherosclerosis	NF-κB signaling pathway
[45]	Circ_0003645	Ox-LDL-induced HUVECs	Inflammation and apoptosis	Atherosclerosis	NF-κB signaling pathway
[46]	IMM-H007	TNF-α-induced HUVECs, THP-1 cells	Endothelial inflammation	Atherosclerosis	NF-κB and JNK/AP1 signaling pathway
[47]	PTP1B	Ox-LDL-induced HUVECs	Endothelial function, inflammation, apoptosis, oxidative stress	Atherosclerosis	AMPK/SIRT1 signaling pathway
[48]	MiR-20a	Ox-LDL-induced HAECs	Inflammation	Atherosclerosis	TLR4 and TXNIP signaling pathways
[49]	CTRP3	Ox-LDL-induced MAECs, ApoE^−/− mice	Endothelial dysfunction, inflammation	Atherosclerosis	PI3K/AKT/eNOS signaling pathway
[50]	ApoM-S1P	TNF-α-induced HUVECs, THP-1 cells	Endothelial cell injury and inflammation, pyroptosis	Atherosclerosis	PI3K/AKT signaling pathway
[51]	VGLL4	Ox-LDL-induced HUVECs	Apoptosis, oxidative stress, inflammation and dysfunction	Atherosclerosis	Hippo-YAP/TEAD1 signaling pathway
[52]	CPEB1	Ox-LDL-induced HUVECs	Oxidative stress, apoptosis, and inflammation	Atherosclerosis	SIRT1/LOX-1 signaling pathway
[53]	Galectin-3	Ox-LDL-induced HUVECs	Endothelial dysfunction	Atherosclerosis	LOX-1/ROS/p38/NF-κB signaling pathway
[54]	MiR-181b	(ApoE)^−/− male rats	Atherosclerotic inflammation	Atherosclerosis	Notch1 signaling pathway
[55]	KRT1, microRNA-107	SPF Kunming mice	Inflammation, apoptosis, and endoplasmic reticulum stress	Coronary atherosclerosis	Notch signaling pathway
[56]	ML7	HFD-fed Rabbits	Endothelial dysfunction and permeability	Atherosclerosis	MAPK signaling pathway
[57]	MicroRNA-216a	Replicative senescence model of HUVECs	Endothelial senescence and inflammation	Atherosclerosis and CAD	Smad3/IκBα signaling pathway
[58]	eADA	LPS-induced HAECs, SC, VSMC, LPS-induced Wistar rats, IL-6^−/− mice	Inflammation	Atherosclerosis	JAK/STAT signaling pathway
[59]	GW4869	BMDCs, LPS-treated DCs, DC-exos-stimulated HUVECs; ApoE^−/−mice	Endothelial inflammation	Atherosclerosis	NF-κB signaling pathway
[60]	Chrysin	IL-1β-induced HUVECs, THP-1 cells, LPS-induced C57BL/6J mice	Endothelial inflammation	Atherosclerosis	NF-κB signaling pathway
[61]	Neferine	IL-1β-induced HUVECs, THP-1cells, LPS-induced C57BL/6 mice	Inflammation	Atherosclerosis	NF-κB signaling pathway
[62]	Triptolide	Ox-LDL-induced HUVECs	Endothelial Inflammation	Atherosclerosis	NF-κB signaling pathway
[63]	S.juice	LPS-induced HUVECs	Inflammation	Atherosclerosis	NF-κB signaling pathway
[64]	Lycosin-I	TNF-α-induced HUVECs, THP-1 cells, LPS-induced C57BL/6 mice	Inflammation	Atherosclerosis	IκB/NF-κB signaling pathway
[65]	Hyperoside	LPS-induced HUVECs	Inflammation and apoptosis	Atherosclerosis	TLR4/NF-κB signaling pathway
[66]	FD	LPS-induced HCAECs	Endothelial activation, inflammation, monocytes adhesion and oxidative stress	Atherosclerosis	NF-κB and eNOS signaling pathways
[67]	Catalpol	Homocysteine-induced HAECs	Oxidation, inflammation, apoptosis, ROS	Hyperhomocyst-einemia	Nox4/NF-κB and GRP78/PERK signaling pathways
[68]	Myristicin	Ox-LDL-induced HUVECs and hVSMCs	Proliferation and apoptosis	Atherosclerosis	PI3K/AKT and NF-κB signaling pathway
[69]	Hypaphorine	LPS-induced HMEC-1	Inflammation	Atherosclerosis	PI3K/AKT/mTORl signaling pathway
[70]	Picroside II	Hyperhomocysteinemia-induced HUVECs and C57BL mice	Inflammation, oxidative stress, apoptosis	Atherosclerosis	SIRT1/LOX-1 signaling pathway
[34]	Active polypeptides from Hirudo	LPS or Ox-LDL-induced HUVECs, RAW264.7, THP-1 cells	Inflammation, ROS, foam cell apoptosis	Atherosclerosis	LOX-1/LXR-α/ABCA1 signaling pathway
[71]	Naringin	Ox-LDL-induced HUVECs	Inflammation and apoptosis	Atherosclerosis	Hippo-YAP signaling pathway
[72]	Melatonin	CSE-induced HAECs	Vascular injury, ROS, pyroptosis	Atherosclerosis	Nrf2/ROS/NLRP3 signaling pathway
[73]	Dihydrohomopla-ntagin and Homoplantaginin	Ox-LDL induced HUVECs, ApoE^−/− mice	Endothelial cell injury, ROS, apoptosis	Atherosclerosis	Nrf2 Anti-Oxidation signaling pathway
[74]	TXNIP	TMAO induced HUVECs	Endothelial dysfunction, inflammation, oxidative stress	Atherosclerosis	ROS-TXINP-NLRP3 signaling pathway
[75]	Rapamycin	Ox-LDL-induced HUVECs	Inflammation	Atherosclerosis	mTORC2/PKC/c-Fos signaling pathway
[76]	Nintedanib	Ox-LDL-induced HUVECs	Inflammation and cellular senescence, oxidative stress	Atherosclerosis	p53/p21 signaling pathway
[77]	TLR4	LPS-induced HUVECs, HEK293FT, THP-1 cells, C57BL/6J mice, Tlr4^mut WT Mice	Inflammation	Atherosclerosis	TLR4 signaling pathway
[78]	NDRG1	Cytokine-stimulated ECs, human and mouse models of AS	Endothelial inflammation and vascular remodeling	Atherosclerosis	NDRG1 pathway
[79]	Isorhynchophylline	HFD-fed ApoE^−/− mice, LPS-treated HUVECs and RAW264.7	Inflammation, cell migration ability	Atherosclerosis	NF-кB/NLRP3 pathway

Abbreviations: HUVECs, human umbilical vein endothelial cells; BMDCs, Bone marrow dendritic cells; DC, Dendritic cells; TNF-a, Tumour necrosis factor-a; KLF14, Krüppel-like factor 14; THP-1, Tohoku Hospital Pediatrics-1; HCAECs, Human coronary artery endothelial cells; Ox-LDL, Oxidized low-density lipoprotein; PTP1B, Protein tyrosine phosphatase 1B; HAECs, Human aortic endothelial cells; CTRP3, C1q/tumor necrosis factor-related protein-3; MAECs, Mouse aortic endothelial cells; VGLL4, Vestigial-like 4; CPEB1, Cytoplasmic polyadenylation element binding protein 1; miR-181b, Micro ribonucleic acid-181b; SPF, specific-pathogen-free Kunming mice; ML7, Myosin light chain kinase inhibitor 7; HFD, high-fat diet; CAD, Coronary artery disease; eADA, Ecto-adenosine deaminase; LPS, Lipopolysaccharide; ROS, Reactive oxygen species; SC, Monocyte/macrophage cells; VSMC, Vascular smooth muscle cells; DC-exos; dendritic cells-derived exosomes; IL-6^−/− mice, IL-6 knock-out mice; FD, Ficus deltoidei; hVSMCs, Human vascular smooth muscle cell; HMEC-1, Human microvascular endothelial cells-1; CSE, cigarette smoke extract; TXNIP, thioredoxin-interactive protein; TMAO, Trimethylamine-N-oxide; Tlr4^mut, Toll-like receptor 4 mutant HeJ mice; WT mice, wild type Heou J mice.

Table 2 Endothelial Inflammation in Cardiovascular Diseases

Ref.	Drug/Targets	Models (cells or animals)	Mechanisms of protection	Diseases	Pathways
[88]	Regular aerobic exercise		Oxidative stress, inflammation	Endothelial dysfunction, large elastic artery stiffening, CVD
[89,90]	IMST		Inflammation, cardiovascular function	CVD
[91]	Apigenin	Vehicle-treated animals	Endothelial dysfunction and large elastic artery stiffening	AS and CVD
[92]	Nicotinamide riboside		Large elastic artery stiffening, oxidative stress, inflammation	CVD
[93]	Women with a history of preeclampsia during pregnancy	Cutaneous microcirculation model	Endothelium-dependent dilation; inflammation	CVD
[94]	Salmonella typhi vaccine	Salmonella typhi vaccine-induced Inflammatory response	Endothelium-dependent dilatation, infections, or inflammation	CVD
[95]	Salicylate	Nitric oxide (NO)-mediated	Endothelium-dependent dilatation, ROS	CVD
[96]	MWCNT	SD rats	Impairment of Coronary Arteriolar Endothelium-Dependent Dilation; inflammation	CVD
[97]	Particulate Matter	Male SD rats	Pulmonary/ microvascular inflammation	CVD
[98]	BAY11-7085	Acute shear stress-induced HUVECs	Endothelial inflammation	Ischaemic heart disease	NF-κB signaling pathway
[99]	Zafirlukast	TNF-α-induced HAECs	Endothelial inflammation, ROS	Cardiovascular diseases	NF-κB signaling pathway
[100]	Schizandrin B	Angiotensin II–induced HUVECs, C57BL/6 mice	Inflammation, oxidative stress	Vascular remodeling	NF-κB signaling pathway
[101]	Epigallocatechin gallate	TNF-α-induced HCAECs	Inflammation	Cardiovascular disease	NF-κB signaling pathway
[102]	MicroRNA-106b, BLNK	Hypoxia-reoxygenation-induced HCMECs and CMECs	Inflammation injury	Endothelial cells dysfunction	NF-κB signaling pathway
[103]	Vitamin D	Ischemia-reperfusion-induced SD rats	Inflammation	Cardiovascular diseases	RhoA/ROCK/NF-ĸB signaling pathway
[104]	4-PBA, TUDCA	ER stress-induced HUVECs, HMECs	Inflammation and apoptosis	Cardiovascular dysfunction	iNOS/NO-NF-κB/IκB and NLRP3 inflammasome pathways
[105]	NAC, STF-083010	Endosulfan-induced HUVECs	Inflammation, dysfunction, oxidative stress, endoplasmic reticulum stress	Cardiovascular diseases	IRE1α/NF-κB signaling pathway
[106]	Orexin A	Ox-LDL-induced HUVECs and HASMCs; THP-1 cells	Inflammation	Cardiovascular diseases	MAPK p38 and NF-κB signaling pathways
[107]	Taxifolin, Cr (VI)	Hexavalent chromium-induced HUVECs, THP-1 cells	Oxidative stress, apoptosis	Cardiovascular diseases	NF-κB and p38 MAPK signaling pathways
[108]	Adiponectin	PA-induced HUVECs	Endothelial inflammation, IR, ROS	Cardiovascular and related diseases	ROS/IKKβ signaling pathway
[109]	QiShenYiQi	HFD fed C57BL/6N mice	Inflammation, oxidative stress	HFpEF	NO-cGMP-PKG signaling pathway
[110]	IMM-H007	TNF-α-induced C57BL/6 mice, HFD fed ApoE^−/−mice, HUVECs	Endothelial dysfunction, inflammation	Cardiovascular diseases	AMPK-PI3K-AKT-eNOS signaling pathway
[111]	Ginsenoside Rg1	Ox-LDL-induced HUVECs	Apoptosis, senescence, oxidative stress	Coronary heart disease	AMPK/SIRT3/p53 signaling pathway
[112]	[1,25 (OH)2D3]	Leptin-induced HUVECs	Oxidative stress and inflammation	Obesity	Nrf2-antioxidant signaling pathway
[113]	Methotrexate	PA-induced SD rats, 3T3-L1 cells	Inflammation	Cardiovascular diseases	AMPK/eNOS signaling pathway

Abbreviations: IMST, Inspiratory Muscle Strength Training; HCMECs, Human cardiac microvascular endothelial cells; CMECs, cardiac microvascular endothelial cells; SD rats, Sprague-Dawley rats; 4-PBA, 4-phenylbutyric acid; TUDCA, tauroursodeoxycholic acid; ER, endoplasmic reticulum; HMECs, human microvessel endothelial cells; NAC, N-acetylcysteine; PA-induced, Palmitic acid-induced; HFpEF, Heart failure with preserved ejection fraction; Cr (VI), Chromium (VI); 1.25 (OH)2D3, 1.25-dihydroxycholecalciferol; IR, Insulin resistance; HASMCs, Human airway smooth muscle cells; NO, nitric oxide; MWCNT, multi-walled carbon nanotube.

Table 3 Endothelial Inflammation in Diabetes Mellitus

Ref.	Drugs/Targets	Models (Cells or Animals)	Mechanisms of Protection	Diseases	Pathways
[122]	MALAT1	HG-induced HUVECs	Inflammation and apoptosis	Diabetes mellitus	NF-κB signaling pathway
[123]	SOX4	HG-induced HRCECs, streptozotocin-induced DB mice	Inflammation	Diabetic retinopathy	NF-κB signaling pathway
[124]	CFTR	HG-induced HUVECs	ROS, inflammation, and apoptosis	Diabetic cardiovascular diseases	NF-κB and MAPK signaling pathways
[125]	hsa_circ_0068087	HG-induced HUVECs	Endothelial dysfunction, inflammation	Diabetes mellitus	TLR4/NF-κB/NLRP3 signaling pathway
[126]	Sgp130	HRECs	Inflammation and apoptosis	Diabetic retinopathy	IL-6 trans-signaling pathway
[127]	MFHAS1	HG-induced HUVECs	Inflammation	Diabetes mellitus	AKT/HO-1 signaling pathway
[128]	TFEB	IL-1β-induced HUVECs, db/db mice	Inflammation	Vascular complications of diabetes	IKK (IκB Kinase)-p65 signaling pathway
[129]	microRNA-9-5p	HG-induced HUVECs	Inflammation and apoptosis	Diabetes mellitus	(MAPK)/ERK and PI3K/AKT/mTOR signaling pathways
[130]	Ketamine	HG-induced HUVECs	Endothelial inflammation, ROS	Perioperative hyperglycemia	NF-κB signaling pathway
[131]	Circulating metabolites of strawberry	db/db mice, HG and palmitate-induced MAECs, WEHI78/24 cells	Endothelial dysfunction, inflammation	Diabetes	NF-κB signaling pathway
[132]	Salidroside	AGEs-induced HUVECs	Endothelial inflammation, oxidative stress, apoptosis	Diabetic conditions	AMPK/NF-κB/NLRP3 signaling pathway
[133]	CCE	PA-induced HUVECs and SD rats	Endothelial inflammation	Insulin resistance	NF-κB and MAPK signaling pathways
[134]	Catalpol	AGEs-induced MGECs, DN mice	Endothelial dysfunction, inflammation	Diabetic nephropathy	RAGE/RhoA/ROCK signaling pathway
[135]	NaHS	HG-induced HUVECs	Injury and inflammation	Diabetes mellitus	p38 MAPK signaling pathway
[136]	Spinosin	PA and insulin-induced HUVECs, HFD fed mice	ROS and inflammation	Diabetes mellitus	PI3K/AKT/ eNOS signaling pathway
[137]	Albiflorin	HG-induced HUVECs	Apoptosis and inflammatory response	Diabetes vascular complications	PARP1/NF-κB signaling pathway

Abbreviations: HRCECs, human retinal endothelial cells; CFTR, Cystic fibrosis transmembrane conductance regulator; sgp130Fc, Soluble gp-130 fused chimera; HRECs Human retinal endothelial cells; MFHAS1, Malignant fibrous histiocytoma amplified sequence 1; TFEB, Transcription factor EB; HG-induced, High-glucose induced; AGEs, advanced glycation end products; CCE, C. chinense.

Table 4 Endothelial Inflammation in Sepsis

Ref.	Drugs/Targets	Models (Cells or Animals)	Mechanisms of Protection	Diseases	Pathways
[147]	hnRNPA2/B1	LPS-induced HUVECs	Endothelial injury	Sepsis	NF-κB and VE-cadherin/β-Catenin pathways
[148]	LPS	LPS-induced PMECs, C57BL/6 mice, TEK/Capn4^−/−, LYZ/Capn4^−/−	Apoptosis, ROS	Acute kidney injury	p38-iNOS signaling pathway
[149]	TRAF6	LPS-induced HUVECs, HLMVECs, YAP-deficient mice	Endothelial dysfunction, inflammation	Sepsis and organ failure	NF-κB signaling pathway
[150]	PD-L1	BEAS-2B cells, LPS-induced HUVECs, mice	Inflammation, apoptosis	Sepsis	HIF-1α signaling pathway
[151]	Rigosertib	LPS-induced C57BL/6 mice	Inflammation	Sepsis	MEK1-ERK signaling pathway
[152]	PCSK9	LPS-treated HUVECs, CLP-induced sepsis model	Inflammation and endothelial dysfunction	Sepsis	TLR4/MyD88/NF-κB and NLRP3 pathways

Abbreviations: TRAF6, Tumor necrosis factor receptor-associated factor 6; PMECs, Pulmonary microvascular endothelial cells; HLMVECs, Human lung microvascular endothelial cells; TEK/Capn4^−/−, Transgenic mice with endothelial-specific Capn4 knockout; LYZ/Capn4^−/−, myeloid-specific Capn4 knockout; CLP, Cecum ligation.

Table 5 Endothelial Inflammation in Respiratory Diseases

Ref.	Drug/Targets	Models (Cells or Animals)	Mechanisms of Protection	Diseases	Pathways
[161]	IL-33, Sox17	Ovalbumin-induced HUVECs, HPMECs, WT mice, Sox17^iΔEC mice, U937 and THP-1 cells	Allergic airway inflammation	Asthma	ERK and STAT3 signaling pathways
[162]	The Antioxidant MitoQ	CSE-induced, HUVECs	Mitochondrial damage, ROS, autophagy, endothelial barrier injury, inflammation	COPD	NF-κB and NLRP3 inflammasome pathways
[163]	microRNA-92a	LPS-induced, HPMECs	Endothelial damage inflammatory	ARDS	PI3K/AKT signaling pathway
[164]	Ghrelin	LPS-induced Mice, EA.hy 926 cells	Inflammation, apoptosis	ARDS	PI3K/AKT signaling pathway
[165]	Ripasudil	LPS-induced PMVECs	Inflammation and apoptosis	ALI	ROCK2/eNOS signaling pathway
[166]	Simvastatin	LPS-induced AECs, Wistar rats	Apoptosis, inflammation	ALI	Survivin/NF-κB/p65 signaling pathway
[167]	Sema3A	LPS-induced PMVECs, rat model of ARDS	Lung injury and inflammation; apoptosis and angiogenesis	ARDS	ERK/JNK signaling pathway

Abbreviations: CSE, Cigarette smoke extract; COPD, Chronic obstructive pulmonary disease; MitoQ, Mitoquinone; HPMECs, Human pulmonary microvascular endothelial cells; ARDS, Acute Respiratory Distress Syndrome; PMVECs, Pulmonary microvascular endothelial cells; ALI, Acute Lung Injury; AECs, Alveolar epithelial cells; WT mice, wild-type mice; Sox17^iΔEC mice, Sox17 knockout mice.

Table 6 Clinical Study of Endothelial Inflammation-Related Diseases

Ref.	Drugs	Dosing Concentrations	Periodicities	SAMPLE SIZES	Diseases	Treatment Effects
[173]	TMYX	40 pills/time, 2 times/day	8 weeks	8	CHD	TMYX improves serum biochemical parameters of patients and effectively suppresses inflammation
[170]	DHA-enriched fish oil	2400 mg/d	8 weeks	50	T2DM	Short-term supplementation with DHA-rich fish oil will protect the cardiovascular system from atherosclerotic lesions and exert its anti-inflammatory effects
[172]	Lp299v	20 billion CFU	6 weeks	20	CAD	Lp299v improves vascular endothelial function and reduces inflammation in patients with CAD
[169]	PEE	500 mg twice daily	8 and 12 weeks	65	MetS	PEE improved endothelial function, oxidative stress, systemic inflammation, and lipid profiles
[174]	PPE and Vit E	225 mg PPE and 400 IU Vit E	8 weeks	100	HD	PPE and vit E improve inflammatory status and endothelial function in HD patients
[168]	TC	250/500 mg twice daily	12 weeks	60	T2DM	TC improves endothelial dysfunction, systemic inflammation, and lipid profile, thereby reducing cardiovascular risk factors in patients with T2DM
[177]	NC	160 mg twice daily	10 days	40	Sepsis	NC has protective effects on inflammation, endothelial function, oxidative stress and biochemical factors in sepsis patients
[175]	CR	6MWT	12 weeks	120	CHF	CR improve the inflammatory status of patients with CHF
[176]	Ticagrelor	n=23	1-month	46	CAD/COPD	Ticagrelor reduces systemic inflammation and oxidative stress in CAD/COPD patients
[171]	O3FAs	4g daily of either EPA, DHA, fish oil (2:1 EPA: DHA)	30 days	40	Atherosclerosis	O3FAs improve vascular inflammation and reduce the development of atherosclerosis

Abbreviations: TMYX, Tongmai Yangxin Pill; CHD, Coronary heart disease; T2DM, Type 2 diabetes mellitus; Lp299v, Lactobacillus Plantarum 299v; CAD, Coronary artery disease; CFU, Colony forming unit; MetS, Metabolic syndrome; PEE, P. emblica aqueous extract; HD, Hemodialysis PPE, Pomegranate peel extract; Vit E, Vitamin E; IU, International unit; TC, Terminalia chebula; NC, nano curcumin; CHF, Chronic heart failure; CR, Cardiac rehabilitation; 6MWT, 6-minute walk test; COPD, Concomitant chronic obstructive pulmonary disease; O3FAs, Omega-3 fatty acids; EPA, Eicosapentaenoic acid; DHA, Docosahexaenoic acid.

Table 7 Directions for Mechanistic Studies in Different Cell Models

Cells	Mechanisms of Protection
HUVECs	Endothelial inflammation, Oxidative stress, Insulin resistance; ROS, Apoptosis, Endothelial injury, Allergic airway inflammation, Autophagy, Permeability, Cellular senescence, Proliferation, Endoplasmic reticulum stress, Mitochondrial damage
HAECs	Inflammation, ROS, Oxidation, Apoptosis, Vascular injury, Pyroptosis
THP-1	Endothelial inflammation, Pyroptosis, Oxidative stress, Apoptosis, ROS
HCAECs	Endothelial activation, Inflammation, Monocytes adhesion, Oxidative stress
Others	Inflammation, Endothelial dysfunction, Apoptosis, ROS, Endothelial senescence, Proliferation, Allergic airway inflammation

Figure 1 Relationship between endothelial cells inflammation models and related diseases.

Figure 2 Signaling pathways involved in the regulation of endothelial cells inflammation.

Table 8 Research Gaps and Future Directions in Endothelial Cells Inflammation in Vascular-Related Diseases

Issue	Research Gaps	Future Directions
Transformation	Translation between basic experimental research and clinical research is challenging	Conducting multi-center and diverse clinical trials to further improve endothelial cell inflammation in vascular-related diseases
Protection mechanisms	Better understanding of how ECs inflammation is manifested in people with vascular-related diseases (AS, CVD, DM, sepsis, RD)	These mechanisms largely serve as potential targets for the treatment of diseases
Propaganda channels	Widely publicize effective interventions for the treatment of vascular-related diseases (AS, CVD, DM, sepsis, RD)	Using the Internet and other means to spread among people with vascular related-diseases and high-risk groups

Figure 3 Inflammation- Vascular- Disease- Pathological States.

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