Abstract
Transforming growth factor-beta 1 (TGF-β1)-mediated tissue fibrosis is an important
regulator of lymphatic dysfunction in secondary lymphedema. However, TGF-β1 targeting
can cause toxicity and autoimmune complications, limiting clinical utility. Angiotensin
II (Ang II) modulates intracellular TGF-β1 signaling, and inhibition of Ang II production
using angiotensin-converting enzyme (ACE) inhibitors, such as captopril, has antifibrotic
efficacy in some pathological settings. Therefore, we analyzed the expression of ACE
and Ang II in clinical lymphedema biopsy specimens from patients with unilateral breast
cancer-related lymphedema (BCRL) and mouse models, and found that cutaneous ACE expression
is increased in lymphedematous tissues. Furthermore, topical captopril decreases fibrosis,
activation of intracellular TGF-β1 signaling pathways, inflammation, and swelling
in mouse models of lymphedema. Captopril treatment also improves lymphatic function
and immune cell trafficking by increasing collecting lymphatic pumping. Our results
show that the renin-angiotensin system in the skin plays an important role in the
regulation of fibrosis in lymphedema, and inhibition of this signaling pathway may
hold merit for treating lymphedema.
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to Translational ResearchAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Estimating the population burden of lymphedema.Ann N Y Acad Sci. 2008; 1131: 147-154
- Lymphedema beyond breast cancer: a systematic review and meta-analysis of cancer-related secondary lymphedema.Cancer. 2010; 116 (p): 5138-5149
- Lymphedema: Pathogenesis and Novel Therapies.Annu Rev Med. 2018; 69: 263-276
- Fibrosis and secondary lymphedema: chicken or egg?.Transl Res. 2019; 209: 68-76
- Pathological steps of cancer-related lymphedema: histological changes in the collecting lymphatic vessels after lymphadenectomy.PLoS One. 2012; 7: e41126
- Blockade of transforming growth factor-beta1 accelerates lymphatic regeneration during wound repair.Am J Pathol. 2010; 177: 3202-3214
- Role of transforming growth factor beta in human disease.N Engl J Med. 2000; 342: 1350-1358
- TGF-β: the master regulator of fibrosis.Nat Rev Nephrol. 2016; 12: 325-338
- Potential role of transforming growth factor-beta 1/Smad signaling in secondary lymphedema after cancer surgery.Cancer Sci. 2020; 111: 2620-2634
- TGF-β1 mediates pathologic changes of secondary lymphedema by promoting fibrosis and inflammation.Clin Transl Med. 2022; 12: e758
- Pathobiology of transforming growth factor beta in cancer, fibrosis and immunologic disease, and therapeutic considerations.Lab Invest. 2007; 87: 1077-1091
- The renin-angiotensin system: going beyond the classical paradigms.Am J Physiol Heart Circ Physiol. 2019; 316: H958-h970
- Cutaneous tissue angiotensin-converting enzyme may participate in pathologic scar formation in human skin.J Am Acad Dermatol. 2006; 54: 251-257
- Modulation of angiotensin II signaling in the prevention of fibrosis.Fibrogenesis Tissue Repair. 2015; 8: 7
- Telmisartan delays myocardial fibrosis in rats with hypertensive left ventricular hypertrophy by TGF-β1/Smad signal pathway.Hypertens Res. 2014; 37: 43-49
- Angiotensin-converting enzyme inhibition attenuates the progression of rat hepatic fibrosis.Gastroenterology. 2001; 121: 148-155
- Inhibition of TGFbeta1 by anti-TGFbeta1 antibody or lisinopril reduces thyroid fibrosis in granulomatous experimental autoimmune thyroiditis.J Immunol. 2002; 169: 6530-6538
- Angiotensin-Converting Enzyme Inhibitor (ACEI)-mediated amelioration in renal fibrosis involves suppression of mast cell degranulation.Kidney Blood Press Res. 2016; 41: 108-118
- Angiotensin-converting enzyme inhibitor reduces scar formation by inhibiting both canonical and noncanonical TGF-β1 pathways.Sci Rep. 2018; 8: 3332
- Impact of inhibitors of the Renin-Angiotensin-aldosterone system on liver fibrosis and portal hypertension.Curr Med Chem. 2006; 13: 3649-3661
- The effect of ACE inhibitors on the expression of matrix genes and the role of p53 and p21 (WAF1) in experimental renal fibrosis.Kidney Int Suppl. 1996; 54: S83-S87
- Prevention of fibrosis in experimental colitis by captopril: the role of tgf-beta1.Inflamm Bowel Dis. 2004; 10: 536-545
- The renin-angiotensin system in experimental radiation nephropathy.J Lab Clin Med. 2002; 139: 251-257
- Epoxyeicosatrienoic acid analogue mitigates kidney injury in a rat model of radiation nephropathy.Clin Sci (Lond). 2016; 130: 587-599
- Treatment of a Postburn Keloid scar with topical captopril: report of the first case.Plastic and Reconstructive Surgery. 2009; 123: 112e-113e
- CD4(+) T cells are activated in regional lymph nodes and migrate to skin to initiate lymphedema.Nat Commun. 2018; 9: 1970
- CD4(+) cells regulate fibrosis and lymphangiogenesis in response to lymphatic fluid stasis.PLoS One. 2012; 7: e49940
- Baseline lymphatic dysfunction amplifies the negative effects of lymphatic injury.Plast Reconstr Surg. 2019; 143: 77e-87e
- TGF-beta1 is a negative regulator of lymphatic regeneration during wound repair.Am J Physiol Heart Circ Physiol. 2008; 295: H2113-H2127
- Secondary lymphedema in the mouse tail: Lymphatic hyperplasia, VEGF-C upregulation, and the protective role of MMP-9.Microvasc Res. 2006; 72: 161-171
- Th2 differentiation is necessary for soft tissue fibrosis and lymphatic dysfunction resulting from lymphedema.Faseb j. 2013; 27: 1114-1126
- Leukotriene B(4) antagonism ameliorates experimental lymphedema.Sci Transl Med. 2017; 9: 3920
- Anti-inflammatory pharmacotherapy with ketoprofen ameliorates experimental lymphatic vascular insufficiency in mice.PLoS One. 2009; 4: e8380
- Regulatory T cell transfer ameliorates lymphedema and promotes lymphatic vessel function.JCI Insight. 2016; 1: e89081
- Inflammatory manifestations of experimental lymphatic insufficiency.PLoS Med. 2006; 3: e254
- Prominent lymphatic vessel hyperplasia with progressive dysfunction and distinct immune cell infiltration in lymphedema.Am J Pathol. 2016; 186: 2193-2203
- Morphological and immunochemical differences between keloid and hypertrophic scar.Am J Pathol. 1994; 145: 105-113
- Use of a PEG-conjugated bright near-infrared dye for functional imaging of rerouting of tumor lymphatic drainage after sentinel lymph node metastasis.Biomaterials. 2013; 34: 5128-5137
- Lymph node T cell homeostasis relies on steady state homing of dendritic cells.Immunity. 2011; 35: 945-957
- Hyperkeratosis in human lower limb lymphedema: the effect of stagnant tissue fluid/lymph.J Eur Acad Dermatol Venereol. 2016; 30: 1002-1008
- The pathophysiology of lymphedema - 2012.Handchir Mikrochir Plast Chir. 2012; 44: 322-328
- Excess lymphangiogenesis cooperatively induced by macrophages and CD4(+) T cells drives the pathogenesis of lymphedema.J Invest Dermatol. 2016; 136: 706-714
- Axial stretch regulates rat tail collecting lymphatic vessel contractions.Sci Rep. 2020; 10: 5918
- The effects of gravity and compression on interstitial fluid transport in the lower limb.Sci Rep. 2022; 12: 4890
- Impaired lymphatic contraction associated with immunosuppression.Proc Natl Acad Sci U S A,. 2011; 108: 18784-18789
- Dynamics of lymphatic regeneration and flow patterns after lymph node dissection.Breast Cancer Res Treat. 2013; 139: 81-86
- Spatio-temporal changes of lymphatic contractility and drainage patterns following lymphadenectomy in mice.PLoS One. 2014; 9e106034
- Inflammatory manifestations of lymphedema.Int J Mol Sci. 2017; 18: 171
- Local angiotensin II aggravates cardiac remodeling in hypertension.Am J Physiol Heart Circ Physiol. 2010; 299: H1328-H1338
- Renin angiotensin aldosterone system in pulmonary fibrosis: Pathogenesis to therapeutic possibilities.Pharmacol Res. 2021; 174105924
- Myocardial fibrosis in response to Angiotensin II is preceded by the recruitment of mesenchymal progenitor cells.Lab Invest. 2011; 91: 565-578
- Physiology of local renin-angiotensin systems.Physiol Rev. 2006; 86: 747-803
- Tissue angiotensin system in cardiovascular medicine. A paradigm shift?.Circulation. 1994; 89: 493-498
- Is there a local renin-angiotensin system in the heart?.Cardiovasc Res. 1999; 44: 252-265
- Angiotensin II induces skin fibrosis: a novel mouse model of dermal fibrosis.Arthritis Res Ther. 2012; 14: R194
- Angiotensin II in the lesional skin of systemic sclerosis patients contributes to tissue fibrosis via angiotensin II type 1 receptors.Arthritis Rheum. 2004; 50: 216-226
- Treatment of a postburn keloid scar with topical captopril: report of the first case.Plast Reconstr Surg. 2009; 123: 112e-113e
- Age-related progressive renal fibrosis in rats and its prevention with ACE inhibitors and taurine.Am J Physiol Renal Physiol. 2000; 278: F122-F129
- Angiotensin-converting-enzyme 2 inhibits liver fibrosis in mice.Hepatology. 2009; 50: 929-938
- Angiotensin Converting Enzyme Inhibitors (ACEIs) decrease the progression of cardiac fibrosis in rheumatic heart disease through the inhibition of IL-33/sST2.Front Cardiovasc Med. 2020; 7: 115
- Transanal delivery of angiotensin converting enzyme inhibitor prevents colonic fibrosis in a mouse colitis model: development of a unique mode of treatment.Surgery. 2008; 144: 259-268
- Angiotensin II and renal fibrosis.Hypertension. 2001; 38 (Pt 2): 635-638
- Nicotinamide adenine dinucleotide phosphate reduced oxidase 5 (Nox5) regulation by angiotensin II and endothelin-1 is mediated via calcium/calmodulin-dependent, rac-1-independent pathways in human endothelial cells.Circ Res. 2010; 106: 1363-1373
- Angiotensin II stimulates cardiac myocyte hypertrophy via paracrine release of TGF-beta 1 and endothelin-1 from fibroblasts.Cardiovasc Res. 1998; 40: 352-363
- Angiotensin II stimulated expression of transforming growth factor-beta1 in cardiac fibroblasts and myofibroblasts.J Mol Cell Cardiol. 1997; 29: 1947-1958
- Effects of an AT1 receptor antagonist, an ACE inhibitor and a calcium channel antagonist on cardiac gene expressions in hypertensive rats.Br J Pharmacol. 1996; 118: 549-556
- Effects of combination of angiotensin-converting enzyme inhibitor and angiotensin receptor antagonist on inflammatory cellular infiltration and myocardial interstitial fibrosis after acute myocardial infarction.J Am Coll Cardiol. 2001; 38: 1207-1215
- Angiotensin II, transforming growth factor-beta1 and repair in the infarcted heart.J Mol Cell Cardiol. 1998; 30: 1559-1569
- TGF-beta1 mediates the hypertrophic cardiomyocyte growth induced by angiotensin II.J Clin Invest. 2002; 109: 787-796
- JunD and HIF-1alpha mediate transcriptional activation of angiotensinogen by TGF-beta1 in human lung fibroblasts.Faseb j. 2009; 23: 1655-1662
- Increased types I and III collagen and transforming growth factor-beta 1 mRNA and protein in hypertrophic burn scar.J Invest Dermatol. 1995; 104: 750-754
- Angiotensin II induces type I collagen gene expression in human dermal fibroblasts through an AP-1/TGF-beta1-dependent pathway.Biochem Biophys Res Commun. 2009; 385: 418-423
- Angiotensin AT1/AT2 receptors: regulation, signalling and function.Blood Press. 2003; 12: 70-88
- International union of pharmacology. XXIII. The angiotensin II receptors.Pharmacol Rev. 2000; 52: 415-472
- Essential role of Smad3 in angiotensin II-induced vascular fibrosis.Circ Res. 2006; 98: 1032-1039
- TGF-beta-induced SMAD signaling and gene regulation: consequences for extracellular matrix remodeling and wound healing.J Dermatol Sci. 2004; 35: 83-92
- Should an angiotensin-converting enzyme inhibitor be standard therapy for patients with atherosclerotic disease?.J Am Coll Cardiol. 2001; 37: 1-8
- Genotypic variation in the transforming growth factor-beta1 gene: association with transforming growth factor-beta1 production, fibrotic lung disease, and graft fibrosis after lung transplantation.Transplantation. 1998; 66: 1014-1020
- Amelioration of radiation-induced fibrosis: inhibition of transforming growth factor-beta signaling by halofuginone.J Biol Chem. 2004; 279: 15167-15176
- Genetic removal of basal nitric oxide enhances contractile activity in isolated murine collecting lymphatic vessels.J Physiol. 2013; 591: 2139-2156
- Regional variations of contractile activity in isolated rat lymphatics.Microcirculation. 2004; 11: 477-492
- Characterization of intact mesenteric lymphatic pump and its responsiveness to acute edemagenic stress.Am J Physiol. 1989; 257 (Pt 2): H2059-H2069
- Topical tacrolimus for the treatment of secondary lymphedema.Nat Commun. 2017; 8: 14345
- Angiotensin II stimulates the proliferation and migration of lymphatic endothelial cells through angiotensin type 1 receptors.Front Physiol. 2020; 11560170
- Effects of angiotensin-converting enzyme inhibitors and angiotensin II type 1 receptor blockers on lymphangiogenesis of gastric cancer in a nude mouse model.Chin Med J (Engl). 2008; 121: 2167-2171
- Lymphatic function is regulated by a coordinated expression of lymphangiogenic and anti-lymphangiogenic cytokines.Am J Physiol Cell Physiol. 2012; 302: C392-C404
- An important role of VEGF-C in promoting lymphedema development.J Invest Dermatol. 2017; 137: 1995-2004
- Higher vascular endothelial growth factor-C concentration in plasma is associated with increased forearm capillary filtration capacity in breast cancer-related lymphedema.Physiol Rep. 2015; 3: e12403
Article info
Publication history
Published online: February 01, 2023
Accepted:
January 25,
2023
Received in revised form:
January 15,
2023
Received:
August 19,
2022
Publication stage
In Press Journal Pre-ProofIdentification
Copyright
© 2023 Elsevier Inc. All rights reserved.
