# Endothelin-1 and Vasomotor Tone Following Cardioplegic Ischemia/Reperfusion and Cardiopulmonary Bypass

**Authors:** Shawn Kant, Frank Sellke, Jun Feng

PMC · DOI: 10.3390/cells15040346 · 2026-02-14

## TL;DR

Endothelin-1 plays a key role in regulating blood vessel tone, and its abnormal activity after heart surgery may contribute to vascular dysfunction, suggesting new treatment possibilities.

## Contribution

This review highlights endothelin-1's role in vasomotor dysfunction after cardiac surgery and identifies it as a potential therapeutic target.

## Key findings

- Endothelin-1 activity is dysregulated in multiple vascular beds after cardiopulmonary bypass.
- Aberrant endothelin-1 signaling may contribute to postoperative vasomotor dysfunction.
- Targeting endothelin-1 pathways could reduce postoperative complications.

## Abstract

What are the main findings?
Endothelin-1 is an important regulator of vasomotor tone in the human bodyAbnormal endothelin-1 activity can be observed in several tissue beds following cardiac surgery involving cardiopulmonary bypass, including the systemic, coronary, skeletal muscle, mesenteric, and pulmonary circulations

Endothelin-1 is an important regulator of vasomotor tone in the human body

Abnormal endothelin-1 activity can be observed in several tissue beds following cardiac surgery involving cardiopulmonary bypass, including the systemic, coronary, skeletal muscle, mesenteric, and pulmonary circulations

What are the implications of the main findings?
Additional research is required to clarify some conflicting data regarding the nature of endothelin-1 dysfunction in certain vascular beds, such as in the coronary and skeletal microcirculationsAberrant endothelin-1 activity and signaling may be a potential therapeutic target for addressing postoperative vasomotor dysfunction following cardiac surgery involving cardiopulmonary bypass

Additional research is required to clarify some conflicting data regarding the nature of endothelin-1 dysfunction in certain vascular beds, such as in the coronary and skeletal microcirculations

Aberrant endothelin-1 activity and signaling may be a potential therapeutic target for addressing postoperative vasomotor dysfunction following cardiac surgery involving cardiopulmonary bypass

Endothelin-1 is a potent regulator of vasomotor tone and promotes endothelium-dependent vasoconstriction of vascular smooth muscle. Dysregulated vasomotor tone is a hallmark of microvascular pathology following cardiac surgery involving cardioplegia and cardiopulmonary bypass (CPB). This review begins with a discussion of the molecular biology of endothelin-1, the structure and function of endothelin receptors, and an overview of endothelin signaling pathways and endogenous regulation. Following this, the focus will turn to an exploration of abnormal endothelin-1 activity during and after CPB across different vascular systems, including coronary, pulmonary, skeletal muscle, peripheral, and mesenteric circulation. Finally, this review concludes with a discussion of drugs targeting endothelin-1 signaling pathways to protect vasomotor tone and microvascular function from ischemia/reperfusion-induced damage, highlighting new therapeutic targets to reduce postoperative morbidity and mortality.

## Full-text entities

- **Genes:** EDN1 (endothelin 1) [NCBI Gene 1906] {aka ARCND3, ET1, HDLCQ7, PPET1, QME}, VEZF1 (vascular endothelial zinc finger 1) [NCBI Gene 7716] {aka CMD1OO, DB1, ZNF161}, CXCL8 (C-X-C motif chemokine ligand 8) [NCBI Gene 3576] {aka GCP-1, GCP1, IL8, LECT, LUCT, LYNAP}, TXK (TXK tyrosine kinase) [NCBI Gene 7294] {aka BTKL, PSCTK5, PTK4, RLK, TKL}, EDN1 (endothelin 1) [NCBI Gene 281137], TNF (tumor necrosis factor) [NCBI Gene 280943] {aka TNF-a, TNF-alpha, TNFa}, SMAD4 (SMAD family member 4) [NCBI Gene 4089] {aka DPC4, JIP, MADH4, MYHRS}, TNF (tumor necrosis factor) [NCBI Gene 7124] {aka DIF, IMD127, TNF-alpha, TNFA, TNFSF2, TNLG1F}, AKT1 (AKT serine/threonine kinase 1) [NCBI Gene 207] {aka AKT, PKB, PKB-ALPHA, PRKBA, RAC, RAC-ALPHA}, IL1A (interleukin 1 alpha) [NCBI Gene 3552] {aka IL-1 alpha, IL-1A, IL1, IL1-ALPHA, IL1F1}, HSPG2 (heparan sulfate proteoglycan 2) [NCBI Gene 3339] {aka HSPG, PLC, PRCAN, SJA, SJS, SJS1}, MPO (myeloperoxidase) [NCBI Gene 100517120], GPR166P (G protein-coupled receptor 166, pseudogene) [NCBI Gene 442206] {aka GPCR, PGR9}, EP300 (EP300 lysine acetyltransferase) [NCBI Gene 2033] {aka KAT3B, MKHK2, RSTS2, p300}, COX2 (cytochrome c oxidase subunit II) [NCBI Gene 4513] {aka COII, MTCO2}, INS (insulin) [NCBI Gene 3630] {aka IDDM, IDDM1, IDDM2, ILPR, IRDN, MODY10}, EDN2 (endothelin 2) [NCBI Gene 1907] {aka ET-2, ET2, PPET2}, F2 (coagulation factor II, thrombin) [NCBI Gene 2147] {aka PT, RPRGL2, THPH1}, PIK3CB (phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta) [NCBI Gene 5291] {aka P110BETA, PI3K, PI3KBETA, PIK3C1}, GSK3B (glycogen synthase kinase 3 beta) [NCBI Gene 2932], JUNB (JunB proto-oncogene, AP-1 transcription factor subunit) [NCBI Gene 3726] {aka AP-1}, EDN3 (endothelin 3) [NCBI Gene 1908] {aka ET-3, ET3, HSCR4, PPET3, WS4B}, PPARG (peroxisome proliferator activated receptor gamma) [NCBI Gene 5468] {aka CIMT1, FPLD3, GLM1, NR1C3, PPARG1, PPARG2}, EDNRA (endothelin receptor type A) [NCBI Gene 1909] {aka ET-A, ETA, ETA-R, ETAR, ETRA, MFDA}, TGFBR1 (transforming growth factor beta receptor 1) [NCBI Gene 7046] {aka AAT5, ACVRLK4, ALK-5, ALK5, ESS1, LDS1}, CMA1 (chymase 1) [NCBI Gene 1215] {aka CYH, MCT1, chymase}, NOS3 (nitric oxide synthase 3) [NCBI Gene 4846] {aka EC-NOS, ECNOS, MYMY8, NOSIII, cNOS, eNOS}, SMAD3 (SMAD family member 3) [NCBI Gene 4088] {aka HSPC193, HsT17436, JV15-2, LDS1C, LDS3, MADH3}, NFKBIA (NFKB inhibitor alpha) [NCBI Gene 4792] {aka EDAID2, IKBA, MAD-3, NFKBI}, HIF1A (hypoxia inducible factor 1 subunit alpha) [NCBI Gene 3091] {aka HIF-1-alpha, HIF-1A, HIF-1alpha, HIF1, HIF1-ALPHA, MOP1}, ARNT (aryl hydrocarbon receptor nuclear translocator) [NCBI Gene 405] {aka ARNT1, HIF-1-beta, HIF-1beta, HIF1-beta, HIF1B, HIF1BETA}, ERVK-3 (endogenous retrovirus group K member 3) [NCBI Gene 100862689] {aka c3_B}, CREBBP (CREB binding lysine acetyltransferase) [NCBI Gene 1387] {aka CBP, KAT3A, MKHK1, RSTS, RSTS1}, BCL2 (BCL2 apoptosis regulator) [NCBI Gene 596] {aka Bcl-2, PPP1R50}, EDN1 (endothelin 1) [NCBI Gene 396915] {aka EDN, ET-1, ET1, PPET1}, IL6 (interleukin 6) [NCBI Gene 3569] {aka BSF-2, BSF2, CDF, HGF, HSF, IFN-beta-2}, EDNRB (endothelin receptor type B) [NCBI Gene 1910] {aka ABCDS, ET-B, ET-BR, ETB, ETB1, ETBR}, PRRT2 (proline rich transmembrane protein 2) [NCBI Gene 112476] {aka BFIC2, BFIS2, DSPB3, DYT10, EKD1, FICCA}, AVP (arginine vasopressin) [NCBI Gene 551] {aka ADH, ARVP, AVP-NPII, AVRP, VP}, PRKCA (protein kinase C alpha) [NCBI Gene 5578] {aka AAG6, PKC-alpha, PKCA, PKCI+/-, PKCalpha}, MPO (myeloperoxidase) [NCBI Gene 4353], ECE1 (endothelin converting enzyme 1) [NCBI Gene 1889] {aka ECE}, TGFB1 (transforming growth factor beta 1) [NCBI Gene 7040] {aka CAEND1, CED, DPD1, IBDIMDE, LAP, TGF-beta1}, AGT (angiotensinogen) [NCBI Gene 183] {aka ANHU, SERPINA8, hFLT1}
- **Diseases:** acute stroke (MESH:D020521), myocardial strain/injury (MESH:D013180), microvascular and organ dysfunction (MESH:D009102), vasomotor dysfunction (MESH:D012223), obese (MESH:D009765), Hypoxic (MESH:D002534), left ventricular dysfunction (MESH:D018487), vasospasm (MESH:D020301), hypoxia (MESH:D000860), pulmonary embolism (MESH:D011655), hypotension (MESH:D007022), Cardioplegic Ischemia (MESH:D007511), metabolic diseases (MESH:D008659), congenital malformations (OMIM:163000), injury to (MESH:D014947), shock (MESH:D012769), inflammation (MESH:D007249), CPB (MESH:D006323), mesenteric ischemia (MESH:D065666), diabetes (MESH:D003920), ischemic (MESH:D002545), vascular disease (MESH:D014652), liver injury (MESH:D017093), cardiac mass (MESH:D006331), thromboembolism (MESH:D013923), vasoplegia (MESH:D056987), pulmonary hypertension (MESH:D006976), atherosclerosis (MESH:D050197), hypertension (MESH:D006973), microvascular dysfunction (MESH:D017566), reperfusion injury (MESH:D015427), hypothermia (MESH:D007035), hyperinsulinemic and insulin-resistance (MESH:D007333), ischemic injury (MESH:D017202), myocardial infarction (MESH:D009203)
- **Chemicals:** thromboxane A2 (MESH:D013928), arachidonic acid (MESH:D016718), methylprednisolone (MESH:D008775), val (MESH:D014633), IP3 (MESH:D015544), leu (MESH:D007930), tyr (MESH:D014443), infliximab (MESH:D000069285), ethanol (MESH:D000431), Nitric oxide (MESH:D009569), glu (MESH:D018698), PGI2 (MESH:D011464), norepinephrine (MESH:D009638), Oxygen (MESH:D010100), sitaxsentan (MESH:C106276), met (MESH:D008715), cGMP (MESH:D006152), epinephrine (MESH:D004837), Aldosterone (MESH:D000450), histidine (MESH:D006639), ile (MESH:D007532), PIP2 (MESH:D019269), lipid (MESH:D008055), Cys (MESH:D003545), glutathione (MESH:D005978), Calcium (MESH:D002118), reactive oxygen species (MESH:D017382), alcohol (MESH:D000438), trp (MESH:D014364), DAG (MESH:D004075), heparin (MESH:D006493), lys (MESH:D008239), sodium (MESH:D012964), disulfide (MESH:D004220), potassium (MESH:D011188), ETA antagonists (-), superoxide (MESH:D013481), Bosentan (MESH:D000077300), phosphatidylcholine (MESH:D010713), phe (MESH:D010649), ser (MESH:D012694), nitrite (MESH:D009573), homocysteine (MESH:D006710), asp (MESH:D001224)
- **Species:** Sus scrofa (pig, species) [taxon 9823], Bos taurus (bovine, species) [taxon 9913], Homo sapiens (human, species) [taxon 9606], Rattus norvegicus (brown rat, species) [taxon 10116]

## Figures

3 figures with captions in the complete paper: https://tomesphere.com/paper/PMC12939322/full.md

---
Source: https://tomesphere.com/paper/PMC12939322