# Pathological mechanisms and clinical research progress of endothelial dysfunction

**Authors:** Zhuoran Wang, Yuqiao Yang, Quan Wang, Lingyan Wang, Yu Zhao, Xi Qian, Rui Feng, Jinqiao Qian

PMC · DOI: 10.3389/fcvm.2026.1749548 · Frontiers in Cardiovascular Medicine · 2026-02-04

## TL;DR

This review summarizes the causes, effects, and treatments of endothelial dysfunction, a key factor in cardiovascular and metabolic diseases.

## Contribution

The paper provides an updated and comprehensive overview of endothelial dysfunction mechanisms and therapies.

## Key findings

- Endothelial dysfunction is linked to diabetes, atherosclerosis, and cerebrovascular disorders.
- Emerging therapies include stem cell and gene therapy for treating endothelial dysfunction.
- Biomarkers for endothelial dysfunction have clinical significance but also limitations.

## Abstract

Endothelial dysfunction (ED) has emerged as a critical pathological contributor to a variety of cardiovascular and metabolic disorders, garnering increasing attention in recent years. This review presents a comprehensive overview of ED, commencing with its definition and broadened criteria. It delves into the molecular mechanisms underlying ED, including reduced nitric oxide availability, oxidative stress, inflammatory responses, apoptosis of endothelial cells, and the emerging concept of endothelial-mesenchymal transition. Furthermore, we investigate the association between ED and multiple conditions, such as diabetes, atherosclerosis, cerebrovascular disorders, and obstructive sleep apnea, drawing on finding from recent clinical investigations. The review highlights the clinical significance and limitations of various biomarkers associated with ED. Moreover, we explore contemporary pharmacological treatment modalities and pioneering therapeutic strategies to alleviate ED, including small molecule agents, stem cell therapy, and gene therapy. By integrating the most recent discoveries from both fundamental and clinical research, this review aims to establish a robust theoretical framework and provide practical guidelines for the diagnosis, prevention, and management of ED.

## Linked entities

- **Diseases:** diabetes (MONDO:0005015), atherosclerosis (MONDO:0005311), obstructive sleep apnea (MONDO:0007147)

## Full-text entities

- **Genes:** RELA (RELA proto-oncogene, NF-kB subunit) [NCBI Gene 5970] {aka AIF3BL3, CMCU, NFKB3, p65}, SELE (selectin E) [NCBI Gene 6401] {aka CD62E, ELAM, ELAM1, ESEL, LECAM2, selectin-e}, CDKN2B-AS1 (CDKN2B and CDKN2A antisense cis and trans regulatory RNA 1) [NCBI Gene 100048912] {aka 66CTG, ANRIL, CDKN2B-AS, CDKN2BAS, NCRNA00089, PCAT12}, PIK3CB (phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta) [NCBI Gene 5291] {aka P110BETA, PI3K, PI3KBETA, PIK3C1}, SNAI1 (snail family transcriptional repressor 1) [NCBI Gene 6615] {aka SLUGH2, SNA, SNAH, SNAIL, SNAIL1, dJ710H13.1}, HSPA5 (heat shock protein family A (Hsp70) member 5) [NCBI Gene 3309] {aka BIP, GRP78, HEL-S-89n}, CDH5 (cadherin 5) [NCBI Gene 1003] {aka 7B4, CD144}, MIR126 (microRNA 126) [NCBI Gene 406913] {aka MIRN126, miRNA126, mir-126}, PTK2B (protein tyrosine kinase 2 beta) [NCBI Gene 2185] {aka CADTK, CAKB, FADK2, FAK2, PKB, PTK}, LEP (leptin) [NCBI Gene 3952] {aka LEPD, OB, OBS}, ENG (endoglin) [NCBI Gene 2022] {aka END, HHT1, ORW1}, NOS3 (nitric oxide synthase 3) [NCBI Gene 4846] {aka EC-NOS, ECNOS, MYMY8, NOSIII, cNOS, eNOS}, FN1 (fibronectin 1) [NCBI Gene 2335] {aka CIG, ED-B, FINC, FN, FNZ, GFND}, MMP9 (matrix metallopeptidase 9) [NCBI Gene 4318] {aka CLG4B, GELB, MANDP2, MMP-9}, ANGPTL2 (angiopoietin like 2) [NCBI Gene 23452] {aka ARP2, HARP}, TWIST1 (twist family bHLH transcription factor 1) [NCBI Gene 7291] {aka ACS3, BPES2, BPES3, CRS, CRS1, CSO}, CRP (C-reactive protein) [NCBI Gene 1401] {aka PTX1}, IL6 (interleukin 6) [NCBI Gene 3569] {aka BSF-2, BSF2, CDF, HGF, HSF, IFN-beta-2}, NLRP3 (NLR family pyrin domain containing 3) [NCBI Gene 114548] {aka AGTAVPRL, AII, AVP, C1orf7, CIAS1, CLR1.1}, F3 (coagulation factor III, tissue factor) [NCBI Gene 2152] {aka CD142, TF, TFA}, PRKAA1 (protein kinase AMP-activated catalytic subunit alpha 1) [NCBI Gene 5562] {aka AMPK, AMPK alpha 1, AMPKa1}, VCAM1 (vascular cell adhesion molecule 1) [NCBI Gene 7412] {aka CD106, INCAM-100}, SNAI2 (snail family transcriptional repressor 2) [NCBI Gene 6591] {aka SLUG, SLUGH, SLUGH1, SNAIL2, WS2D}, MMP7 (matrix metallopeptidase 7) [NCBI Gene 4316] {aka MMP-7, MPSL1, PUMP-1}, TGFB1 (transforming growth factor beta 1) [NCBI Gene 7040] {aka CAEND1, CED, DPD1, IBDIMDE, LAP, TGF-beta1}, RHOD (ras homolog family member D) [NCBI Gene 29984] {aka ARHD, RHOHP1, RHOM, Rho}, CTNNB1 (catenin beta 1) [NCBI Gene 1499] {aka CTNNB, EVR7, MRD19, NEDSDV, armadillo}, ACTA1 (actin alpha 1, skeletal muscle) [NCBI Gene 58] {aka ACTA, ASMA, CFTD, CFTD1, CFTDM, CMYO2A}, CXCL8 (C-X-C motif chemokine ligand 8) [NCBI Gene 3576] {aka GCP-1, GCP1, IL8, LECT, LUCT, LYNAP}, NFKB1 (nuclear factor kappa B subunit 1) [NCBI Gene 4790] {aka CVID12, EBP-1, KBF1, NF-kB, NF-kB1, NF-kappa-B1}, ANXA5 (annexin A5) [NCBI Gene 308] {aka ANX5, CPB-I, ENX2, HEL-S-7, PP4, RPRGL3}, APOE (apolipoprotein E) [NCBI Gene 348] {aka AD2, APO-E, ApoE4, LDLCQ5, LPG}, EDN1 (endothelin 1) [NCBI Gene 1906] {aka ARCND3, ET1, HDLCQ7, PPET1, QME}, INSR (insulin receptor) [NCBI Gene 3643] {aka CD220, HHF5}, LDLR (low density lipoprotein receptor) [NCBI Gene 3949] {aka LDLCQ2}, ICAM1 (intercellular adhesion molecule 1) [NCBI Gene 3383] {aka BB2, CD54, P3.58}, TEK (TEK receptor tyrosine kinase) [NCBI Gene 7010] {aka CD202B, GLC3E, TIE-2, TIE2, VMCM, VMCM1}, TNNI3 (troponin I3, cardiac type) [NCBI Gene 7137] {aka CMD1FF, CMD2A, CMH7, RCM1, TNNC1, cTnI}, APLN (apelin) [NCBI Gene 8862] {aka APEL, XNPEP2}, ESM1 (endothelial cell specific molecule 1) [NCBI Gene 11082] {aka endocan}, REN (renin) [NCBI Gene 5972] {aka ADTKD4, HNFJ2, RTD}, NOS2 (nitric oxide synthase 2) [NCBI Gene 4843] {aka HEP-NOS, INOS, NOS, NOS2A}, APLNR (apelin receptor) [NCBI Gene 187] {aka AGTRL1, APJ, APJR, HG11}, SIRT1 (sirtuin 1) [NCBI Gene 23411] {aka SIR2, SIR2L1, SIR2alpha}, RHOA (ras homolog family member A) [NCBI Gene 387] {aka ARH12, ARHA, EDFAOB, RHO12, RHOH12}, CALM1 (calmodulin 1) [NCBI Gene 801] {aka CALML2, CAM2, CAM3, CAMB, CAMC, CAMI}, NOTCH1 (notch receptor 1) [NCBI Gene 4851] {aka AOS5, AOVD1, TAN1, hN1}, ADIPOQ (adiponectin, C1Q and collagen domain containing) [NCBI Gene 9370] {aka ACDC, ACRP30, ADIPQTL1, ADPN, APM-1, APM1}, IL18 (interleukin 18) [NCBI Gene 3606] {aka IGIF, IL-18, IL-1g, IL1F4}, RETN (resistin) [NCBI Gene 56729] {aka ADSF, FIZZ3, RENT, RETN1, RSTN, XCP1}, PTPN1 (protein tyrosine phosphatase non-receptor type 1) [NCBI Gene 5770] {aka PTP1B}, AKT1 (AKT serine/threonine kinase 1) [NCBI Gene 207] {aka AKT, PKB, PKB-ALPHA, PRKBA, RAC, RAC-ALPHA}, DDIT3 (DNA damage inducible transcript 3) [NCBI Gene 1649] {aka AltDDIT3, C/EBPzeta, CEBPZ, CHOP, CHOP-10, CHOP10}, TNF (tumor necrosis factor) [NCBI Gene 7124] {aka DIF, IMD127, TNF-alpha, TNFA, TNFSF2, TNLG1F}, INS (insulin) [NCBI Gene 3630] {aka IDDM, IDDM1, IDDM2, ILPR, IRDN, MODY10}, CCL2 (C-C motif chemokine ligand 2) [NCBI Gene 6347] {aka GDCF-2, HC11, HSMCR30, MCAF, MCP-1, MCP1}, IL1B (interleukin 1 beta) [NCBI Gene 3553] {aka IL-1, IL1-BETA, IL1F2, IL1beta}, VIM (vimentin) [NCBI Gene 7431], GLP1R (glucagon like peptide 1 receptor) [NCBI Gene 2740] {aka GLP-1, GLP-1-R, GLP-1R}, PECAM1 (platelet and endothelial cell adhesion molecule 1) [NCBI Gene 5175] {aka CD31, CD31/EndoCAM, GPIIA', PECA1, PECAM-1, endoCAM}
- **Diseases:** OSA (MESH:D020181), type 2 diabetes (MESH:D003924), inflammatory cytokines (MESH:D000080424), impaired peripheral arterial function (MESH:D058729), infarct (MESH:D007238), heart failure (MESH:D006333), nephropathy (MESH:D007674), adipose tissue (MESH:D018205), cardiac, renal, and pulmonary fibrosis (MESH:D011658), systemic (MESH:D015619), CAD (MESH:D003324), compromised heart function (MESH:D006331), neointimal hyperplasia (MESH:D006965), chronic (MESH:D002908), sepsis (MESH:D018805), pulmonary hypertension (MESH:D006976), spasm (MESH:D013035), microvascular dysfunction (MESH:D017566), metastasis (MESH:D009362), thrombotic (MESH:D013927), endotoxemia (MESH:D019446), diabetic cardiomyopathy (MESH:D058065), EndMT (MESH:D008579), hypertension (MESH:D006973), diabetic complications (MESH:D048909), atherogenesis (MESH:D050197), pulmonary arterial hypertension (MESH:D000081029), diabetic microvascular disease (OMIM:612623), myocardial infarction (MESH:D009203), cardiovascular and neurological diseases (MESH:D002318), coagulation (MESH:D001778), gestational hypertension (MESH:D046110), ischemic injury (MESH:D017202), ischemic stroke (MESH:D002544), Endothelial injury (MESH:D057772), cerebrovascular disorders (MESH:D002561), weight loss (MESH:D015431), heart abnormalities (MESH:D006330), Insulin resistance (MESH:D007333), vasomotor dysfunction (MESH:D012223), Obesity (MESH:D009765), hemorrhagic (MESH:D006470), cardiomyopathy (MESH:D009202), diabetic microangiopathy (MESH:D003925), retinopathy (MESH:D058437), stroke (MESH:D020521), hyperemia (MESH:D006940), neurological disorders (MESH:D009461), obstructive (MESH:D000402), ischemia (MESH:D007511), metabolic diseases (MESH:D008659), proteinuria (MESH:D011507), acute ischemic stroke (MESH:D000083242), fibrotic disorders (MESH:D009358), vasospasm (MESH:D020301), systemic diseases (MESH:D034721), hypoxia (MESH:D000860), neurodegenerative diseases (MESH:D019636), fibrotic diseases (MESH:D004194), Inflammation (MESH:D007249)
- **Chemicals:** peroxynitrite (MESH:D030421), LPS (MESH:D008070), Lipid (MESH:D008055), glucose (MESH:D005947), flavonoids (MESH:D005419), ADMA (MESH:C018524), ROS (MESH:D017382), berberine (MESH:D001599), canakinumab (MESH:C541220), O2 - (MESH:D013481), L-NG-nitroarginine methyl ester (-), curcumin (MESH:D003474), perindopril (MESH:D020913), BH4 (MESH:C003402), L-arginine (MESH:D001120), AGEs (MESH:D017127), tyrosine (MESH:D014443), 3-nitrotyrosine (MESH:C002744), free fatty acids (MESH:D005230), acetylcholine (MESH:D000109), streptozotocin (MESH:D013311), dithiothreitol (MESH:D004229), NO (MESH:D009569), cholesterol (MESH:D002784), blood sugar (MESH:D001786), fat (MESH:D005223), cyclic guanosine monophosphate (MESH:D006152), thapsigargin (MESH:D019284), SRT1720 (MESH:C525422), vitamin E (MESH:D014810)
- **Species:** Bos taurus (bovine, species) [taxon 9913], Homo sapiens (human, species) [taxon 9606], Nicotiana tabacum (American tobacco, species) [taxon 4097], Mus musculus (house mouse, species) [taxon 10090]
- **Mutations:** G894T, T-786C

## Full text

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## Figures

2 figures with captions in the complete paper: https://tomesphere.com/paper/PMC12913529/full.md

## References

151 references — full list in the complete paper: https://tomesphere.com/paper/PMC12913529/full.md

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Source: https://tomesphere.com/paper/PMC12913529