Connexins and angiogenesis: Functional aspects, pathogenesis, and emerging therapies (Review)
- Authors:
- Zizi Zhou
- Wenxiang Chai
- Yi Liu
- Meng Zhou
- Xiaoming Zhang
-
Affiliations: Department of Cardio‑Thoracic Surgery, Shenzhen University General Hospital, Shenzhen, Guangdong 518055, P.R. China - Published online on: June 24, 2022 https://doi.org/10.3892/ijmm.2022.5166
- Article Number: 110
-
Copyright: © Zhou et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
This article is mentioned in:
Abstract
Carmeliet P: Mechanisms of angiogenesis and arteriogenesis. Nat Med. 6:389–395. 2000. View Article : Google Scholar : PubMed/NCBI | |
Koepple C, Zhou Z, Huber L, Schulte M, Schmidt K, Gloe T, Kneser U, Schmidt VJ and de Wit C: Expression of Connexin43 Stimulates Endothelial Angiogenesis Independently of Gap junctional communication in vitro. Int J Mol Sci. 22:74002021. View Article : Google Scholar : PubMed/NCBI | |
Haefliger JA, Meda P and Alonso F: Endothelial connexins in developmental and pathological angiogenesis. Cold Spring Harb Perspect Med. 12:a0411582022. View Article : Google Scholar : PubMed/NCBI | |
Qiu Y, Zheng J, Chen S and Sun Y: Connexin mutations and hereditary diseases. Int J Mol Sci. 23:42552022. View Article : Google Scholar : PubMed/NCBI | |
Peracchia C and Leverone Peracchia LM: Calmodulin-Connexin partnership in Gap junction channel regulation-calmodulin-cork gating model. Int J Mol Sci. 22:130552021. View Article : Google Scholar : PubMed/NCBI | |
Okamoto T, Park EJ, Kawamoto E, Usuda H, Wada K, Taguchi A and Shimaoka M: Endothelial connexin-integrin crosstalk in vascular inflammation. Biochim Biophys Acta Mol Basis Dis. 1867:1661682021. View Article : Google Scholar : PubMed/NCBI | |
Laird DW and Lampe PD: Cellular mechanisms of connexin-based inherited diseases. Trends Cell Biol. 32:58–69. 2022. View Article : Google Scholar | |
King DR, Sedovy MW, Leng X, Xue J, Lamouille S, Koval M, Isakson BE and Johnstone SR: Mechanisms of connexin regulating peptides. Int J Mol Sci. 22:101862021. View Article : Google Scholar : PubMed/NCBI | |
Htet M, Nally JE, Martin PE and Dempsie Y: New insights into pulmonary hypertension: A role for connexin-mediated signal- ling. Int J Mol Sci. 23:3792021. View Article : Google Scholar | |
Roy S, Jiang JX, Li AF and Kim D: Connexin channel and its role in diabetic retinopathy. Prog Retin Eye Res. 61:35–59. 2017. View Article : Google Scholar : PubMed/NCBI | |
Nielsen MS, Axelsen LN, Sorgen PL, Verma V, Delmar M and Holstein-Rathlou NH: Gap junctions. Compr Physiol. 2:1981–2035. 2012. View Article : Google Scholar | |
Zhou JZ and Jiang JX: Gap junction and hemichannel-independent actions of connexins on cell and tissue functions-an update. FEBS Lett. 588:1186–1192. 2014. View Article : Google Scholar : PubMed/NCBI | |
Tarzemany R, Jiang G, Jiang JX, Larjava H and Häkkinen L: Connexin 43 hemichannels regulate the expression of wound healing-associated genes in human gingival fibroblasts. Sci Rep. 7:141572017. View Article : Google Scholar : PubMed/NCBI | |
Jacobsen NL, Pontifex TK, Li H, Solan JL, Lampe PD, Sorgen PL and Burt JM: Regulation of Cx37 channel and growth-suppressive properties by phosphorylation. J Cell Sci. 130:3308–3321. 2017.PubMed/NCBI | |
Cocozzelli AG and White TW: Connexin 43 mutations lead to increased hemichannel functionality in skin disease. Int J Mol Sci. 20:61862019. View Article : Google Scholar | |
Mannell H, Kameritsch P, Beck H, Pfeifer A, Pohl U and Pogoda K: Cx43 promotes endothelial cell migration and angiogenesis via the tyrosine phosphatase SHP-2. Int J Mol Sci. 23:2942021. View Article : Google Scholar | |
Falleni A, Moscato S, Sabbatini ARM, Bernardeschi M, Bianchi F, Cecchettini A and Mattii L: Subcellular localization of connexin 26 in cardiomyocytes and in cardiomyocyte-derived extracellular vesicles. Molecules. 26:67262021. View Article : Google Scholar : PubMed/NCBI | |
Wang DG, Zhang FX, Chen ML, Zhu HJ, Yang B and Cao KJ: Cx43 in mesenchymal stem cells promotes angiogenesis of the infarcted heart independent of gap junctions. Mol Med Rep. 9:1095–1102. 2014. View Article : Google Scholar : PubMed/NCBI | |
Moorby C and Patel M: Dual functions for connexins: Cx43 regulates growth independently of gap junction formation. Exp Cell Res. 271:238–248. 2001. View Article : Google Scholar : PubMed/NCBI | |
Sathiyanadan K, Alonso F, Domingos-Pereira S, Santoro T, Hamard L, Cesson V, Meda P, Nardelli-Haefliger D and Haefliger JA: Targeting Endothelial Connexin37 reduces angiogenesis and decreases tumor growth. Int J Mol Sci. 23:29302022. View Article : Google Scholar : PubMed/NCBI | |
Thuringer D, Jego G, Berthenet K, Hammann A, Solary E and Garrido C: Gap junction-mediated transfer of miR-145-5p from microvascular endothelial cells to colon cancer cells inhibits angiogenesis. Oncotarget. 7:28160–28168. 2016. View Article : Google Scholar : PubMed/NCBI | |
Choudhary M, Naczki C, Chen W, Barlow KD, Case LD and Metheny-Barlow LJ: Tumor-induced loss of mural Connexin 43 gap junction activity promotes endothelial proliferation. BMC Cancer. 15:4272015. View Article : Google Scholar : PubMed/NCBI | |
Aasen T, Leithe E, Graham SV, Kameritsch P, Mayán MD, Mesnil M, Pogoda K and Tabernero A: Connexins in cancer: Bridging the gap to the clinic. Oncogene. 38:4429–4451. 2019. View Article : Google Scholar : PubMed/NCBI | |
Distler O, Neidhart M, Gay RE and Gay S: The molecular control of angiogenesis. Int Rev Immunol. 21:33–49. 2002. View Article : Google Scholar : PubMed/NCBI | |
Polverini PJ: The pathophysiology of angiogenesis. Crit Rev Oral Biol Med. 6:230–247. 1995. View Article : Google Scholar : PubMed/NCBI | |
Goel S, Duda DG, Xu L, Munn LL, Boucher Y, Fukumura D and Jain RK: Normalization of the vasculature for treatment of cancer and other diseases. Physiol Rev. 91:1071–1121. 2011. View Article : Google Scholar : PubMed/NCBI | |
Zefferino R, Piccoli C, Gioia SD, Capitanio N and Conese M: Gap junction intercellular communication in the carcinogenesis Hallmarks: Is this a phenomenon or epiphenomenon? Cells. 8:8962019. View Article : Google Scholar : | |
Wang HH, Su CH, Wu YJ, Li JY, Tseng YM, Lin YC, Hsieh CL, Tsai CH and Yeh HI: Reduction of connexin43 in human endothelial progenitor cells impairs the angiogenic potential. Angiogenesis. 16:553–560. 2013. View Article : Google Scholar : PubMed/NCBI | |
Kandasamy K, Escue R, Manna J, Adebiyi A and Parthasarathi K: Changes in endothelial connexin 43 expression inversely correlate with microvessel permeability and VE-cadherin expression in endotoxin-challenged lungs. Am J Physiol Lung Cell Mol Physiol. 309:L584–L592. 2015. View Article : Google Scholar : PubMed/NCBI | |
O'Donnell JJ III, Birukova AA, Beyer EC and Birukov KG: Gap junction protein connexin43 exacerbates lung vascular permeability. PLoS One. 9:e1009312014. View Article : Google Scholar : PubMed/NCBI | |
Salmina AB, Morgun AV, Kuvacheva NV, Lopatina OL, Komleva YK, Malinovskaya NA and Pozhilenkova EA: Establishment of neurogenic microenvironment in the neurovascular unit: The connexin 43 story. Rev Neurosci. 25:97–111. 2014. View Article : Google Scholar : PubMed/NCBI | |
Schmidt VJ, Hilgert JG, Covi JM, Weis C, Wietbrock JO, de Wit C, Horch RE and Kneser U: High flow conditions increase connexin43 expression in a rat arteriovenous and angioinductive loop model. PLoS One. 8:e787822013. View Article : Google Scholar : PubMed/NCBI | |
Gerbaud P and Pidoux G: Review: An overview of molecular events occurring in human trophoblast fusion. Placenta. 36(Suppl 1): S35–S42. 2015. View Article : Google Scholar : PubMed/NCBI | |
He X and Chen Q: Reduced expressions of connexin 43 and VEGF in the first-trimester tissues from women with recurrent pregnancy loss. Reprod Biol Endocrinol. 14:462016. View Article : Google Scholar : PubMed/NCBI | |
Zhang XF and Cui X: Connexin 43: Key roles in the skin. Biomed Rep. 6:605–611. 2017. View Article : Google Scholar : PubMed/NCBI | |
Alonso F, Domingos-Pereira S, Le Gal L, Derré L, Meda P, Jichlinski P, Nardelli-Haefliger D and Haefliger JA: Targeting endothelial connexin40 inhibits tumor growth by reducing angiogenesis and improving vessel perfusion. Oncotarget. 7:14015–14028. 2016. View Article : Google Scholar : PubMed/NCBI | |
Haefliger JA, Allagnat F, Hamard L, Le Gal L, Meda P, Nardelli-Haefliger D, Génot E and Alonso F: Targeting Cx40 (Connexin40) expression or function reduces angiogenesis in the developing mouse retina. Arterioscler Thromb Vasc Biol. 37:2136–2146. 2017. View Article : Google Scholar : PubMed/NCBI | |
Fang JS, Angelov SN, Simon AM and Burt JM: Cx37 deletion enhances vascular growth and facilitates ischemic limb recovery. Am J Physiol Heart Circ Physiol. 301:H1872–H1881. 2011. View Article : Google Scholar : PubMed/NCBI | |
Li H, Spagnol G, Pontifex TK, Burt JM and Sorgen PL: Chemical shift assignments of the connexin37 carboxyl terminal domain. Biomol NMR Assign. 11:137–141. 2017. View Article : Google Scholar : PubMed/NCBI | |
Pogoda K, Füller M, Pohl U and Kameritsch P: NO, via its target Cx37, modulates calcium signal propagation selectively at myoendothelial gap junctions. Cell Commun Signal. 12:332014. View Article : Google Scholar : PubMed/NCBI | |
Fang JS, Angelov SN, Simon AM and Burt JM: Cx40 is required for, and cx37 limits, postischemic hindlimb perfusion, survival and recovery. J Vasc Res. 49:2–12. 2012. View Article : Google Scholar | |
Le Gal L, Pellegrin M, Santoro T, Mazzolai L, Kurtz A, Meda P, Wagner C and Haefliger JA: Connexin37-Dependent mechanisms selectively contribute to modulate Angiotensin II-Mediated Hypertension. J Am Heart Assoc. 8:e0108232019. View Article : Google Scholar | |
Taylor SZ, Jacobsen NL, Pontifex TK, Langlais P and Burt JM: Serine 319 phosphorylation is necessary and sufficient to induce a Cx37 conformation that leads to arrested cell cycling. J Cell Sci. 133:jcs2407212020. View Article : Google Scholar : PubMed/NCBI | |
O'Carroll SJ, Becker DL, Davidson JO, Gunn AJ, Nicholson LF and Green CR: The use of connexin-based therapeutic approaches to target inflammatory diseases. Methods Mol Biol. 1037:519–546. 2013. View Article : Google Scholar : PubMed/NCBI | |
Yu W, Jin H, Sun W, Nan D, Deng J, Jia J, Yu Z and Huang Y: Connexin43 promotes angiogenesis through activating the HIF-1α/VEGF signaling pathway under chronic cerebral hypo- perfusion. J Cereb Blood Flow Metab. 41:2656–2675. 2021. View Article : Google Scholar : PubMed/NCBI | |
Lorraine C, Wright CS and Martin PE: Connexin43 plays diverse roles in co-ordinating cell migration and wound closure events. Biochem Soc Trans. 43:482–488. 2015. View Article : Google Scholar : PubMed/NCBI | |
Hoffmann A, Gloe T, Pohl U and Zahler S: Nitric oxide enhances de novo formation of endothelial gap junctions. Cardiovasc Res. 60:421–430. 2003. View Article : Google Scholar : PubMed/NCBI | |
Li H, He J, Yu H, Green CR and Chang J: Bioglass promotes wound healing by affecting gap junction connexin 43 mediated endothelial cell behavior. Biomaterials. 84:64–75. 2016. View Article : Google Scholar : PubMed/NCBI | |
Zhang K, Chai B, Ji H, Chen L, Ma Y, Zhu L, Xu J, Wu Y, Lan Y, Li H, et al: Bioglass promotes wound healing by inhibiting endothelial cell pyroptosis through regulation of the connexin 43/reactive oxygen species (ROS) signaling pathway. Lab Invest. 102:90–101. 2022. View Article : Google Scholar | |
Faniku C, O'Shaughnessy E, Lorraine C, Johnstone SR, Graham A, Greenhough S and Martin PEM: The connexin mimetic peptide Gap27 and Cx43-Knockdown reveal differential roles for Connexin43 in wound closure events in skin model systems. Int J Mol Sci. 19:6042018. View Article : Google Scholar : | |
Martin PE, Easton JA, Hodgins MB and Wright CS: Connexins: Sensors of epidermal integrity that are therapeutic targets. FEBS Lett. 588:1304–1314. 2014. View Article : Google Scholar : PubMed/NCBI | |
Tarzemany R, Jiang G, Larjava H and Häkkinen L: Expression and function of connexin 43 in human gingival wound healing and fibroblasts. PLoS One. 10:e01155242015. View Article : Google Scholar : PubMed/NCBI | |
Montgomery J, Ghatnekar GS, Grek CL, Moyer KE and Gourdie RG: Connexin 43-Based therapeutics for dermal wound healing. Int J Mol Sci. 19:17782018. View Article : Google Scholar : | |
Arshad M, Conzelmann C, Riaz MA, Noll T and Gündüz D: Inhibition of Cx43 attenuates ERK1/2 activation, enhances the expression of Cav-1 and suppresses cell proliferation. Int J Mol Med. 42:2811–2818. 2018.PubMed/NCBI | |
Wu PC, Hsu WL, Chen CL, Lam CF, Huang YB, Huang CC, Lin MH and Lin MW: Morphine induces fibroblast activation through Up-regulation of Connexin 43 expression: Implication of fibrosis in wound healing. Int J Med Sci. 15:875–882. 2018. View Article : Google Scholar : PubMed/NCBI | |
Asencio-Barría C, Defamie N, Sáez JC, Mesnil M and Godoy AS: Direct intercellular communications and cancer: A snapshot of the biological roles of connexins in prostate cancer. Cancers (Basel). 11:13702019. View Article : Google Scholar | |
Gleisner MA, Navarrete M, Hofmann F, Salazar-Onfray F and Tittarelli A: Mind the Gaps in tumor immunity: Impact of connexin-mediated intercellular connections. Front Immunol. 8:10672017. View Article : Google Scholar : PubMed/NCBI | |
Graham SV, Jiang JX and Mesnil M: Connexins and pannexins: Important players in tumorigenesis, metastasis and potential therapeutics. Int J Mol Sci. 19:16452018. View Article : Google Scholar : | |
Acuña RA, Varas-Godoy M, Herrera-Sepulveda D and Retamal MA: Connexin46 expression enhances cancer stem cell and Epithelial-to-Mesenchymal transition characteristics of human breast cancer MCF-7 cells. Int J Mol Sci. 22:126042021. View Article : Google Scholar : PubMed/NCBI | |
Karpinich NO and Caron KM: Gap junction coupling is required for tumor cell migration through lymphatic endothelium. Arterioscler Thromb Vasc Biol. 35:1147–1155. 2015. View Article : Google Scholar : PubMed/NCBI | |
Fang JS, Coon BG, Gillis N, Chen Z, Qiu J, Chittenden TW, Burt JM, Schwartz MA and Hirschi KK: Shear-induced Notch-Cx37-p27 axis arrests endothelial cell cycle to enable arterial specification. Nat Commun. 8:21492017. View Article : Google Scholar : PubMed/NCBI | |
Wang WK, Chen MC, Leong HF, Kuo YL, Kuo CY and Lee CH: Connexin 43 suppresses tumor angiogenesis by down-regulation of vascular endothelial growth factor via hypoxic-induced factor-1α. Int J Mol Sci. 16:439–451. 2014. View Article : Google Scholar : PubMed/NCBI | |
Schulz R, Görge PM, Görbe A, Ferdinandy P, Lampe PD and Leybaert L: Connexin 43 is an emerging therapeutic target in ischemia/reperfusion injury, cardioprotection and neuroprotection. Pharmacol Ther. 153:90–106. 2015. View Article : Google Scholar : PubMed/NCBI | |
Michela P, Velia V, Aldo P and Ada P: Role of connexin 43 in cardiovascular diseases. Eur J Pharmacol. 768:71–76. 2015. View Article : Google Scholar : PubMed/NCBI | |
Hegner P, Lebek S, Tafelmeier M, Camboni D, Schopka S, Schmid C, Maier LS, Arzt M and Wagner S: Sleep-disordered breathing is independently associated with reduced atrial connexin 43 expression. Heart Rhythm. 18:2187–2194. 2021. View Article : Google Scholar : PubMed/NCBI | |
Ugwu N, Atzmony L, Ellis KT, Panse G, Jain D, Ko CJ, Nassiri N and Choate KA: Cutaneous and hepatic vascular lesions due to a recurrent somatic GJA4 mutation reveal a pathway for vascular malformation. HGG Adv. 2:1000282021. | |
Huang GY, Xie LJ, Linask KL, Zhang C, Zhao XQ, Yang Y, Zhou GM, Wu YJ, Marquez-Rosado L, McElhinney DB, et al: Evaluating the role of connexin43 in congenital heart disease: Screening for mutations in patients with outflow tract anomalies and the analysis of knock-in mouse models. J Cardiovasc Dis Res. 2:206–212. 2011. View Article : Google Scholar : PubMed/NCBI | |
Salameh A, Haunschild J, Bräuchle P, Peim O, Seidel T, Reitmann M, Kostelka M, Bakhtiary F, Dhein S and Dähnert I: On the role of the gap junction protein Cx43 (GJA1) in human cardiac malformations with Fallot-pathology. a study on paediatric cardiac specimen. PLoS One. 9:e953442014. View Article : Google Scholar : PubMed/NCBI | |
Milberg P, Klocke R, Frommeyer G, Quang TH, Dieks K, Stypmann J, Osada N, Kuhlmann M, Fehr M, Milting H, et al: G-CSF therapy reduces myocardial repolarization reserve in the presence of increased arteriogenesis, angiogenesis and connexin 43 expression in an experimental model of pacing-induced heart failure. Basic Res Cardiol. 106:995–1008. 2011. View Article : Google Scholar : PubMed/NCBI | |
Li L, Liu H, Xu C, Deng M, Song M, Yu X, Xu S and Zhao X: VEGF promotes endothelial progenitor cell differentiation and vascular repair through connexin 43. Stem Cell Res Ther. 8:2372017. View Article : Google Scholar : PubMed/NCBI | |
Yu H, Kalogeris T and Korthuis RJ: Reactive species-induced microvascular dysfunction in ischemia/reperfusion. Free Radic Biol Med. 135:182–197. 2019. View Article : Google Scholar : PubMed/NCBI | |
Bellafiore M, Sivverini G, Palumbo D, Macaluso F, Bianco A, Palma A and Farina F: Increased cx43 and angiogenesis in exercised mouse hearts. Int J Sports Med. 28:749–755. 2007. View Article : Google Scholar : PubMed/NCBI | |
Grippo AJ, Moffitt JA, Henry MK, Firkins R, Senkler J, McNeal N, Wardwell J, Scotti MA, Dotson A and Schultz R: Altered Connexin 43 and Connexin 45 protein expression in the heart as a function of social and environmental stress in the prairie vole. Stress. 18:107–114. 2015. View Article : Google Scholar : | |
Vilà-González M, Kelaini S, Magee C, Caines R, Campbell D, Eleftheriadou M, Cochrane A, Drehmer D, Tsifaki M, O'Neill K, et al: Enhanced function of induced pluripotent stem cell-derived endothelial cells through ESM1 signaling. Stem Cells. 37:226–239. 2019. View Article : Google Scholar | |
Su F, Zhao L, Zhang S, Wang J, Chen N, Gong Q, Tang J, Wang H, Yao J, Wang Q, et al: Cardioprotection by PI3K-mediated signaling is required for anti-arrhythmia and myocardial repair in response to ischemic preconditioning in infarcted pig hearts. Lab Invest. 95:860–871. 2015. View Article : Google Scholar : PubMed/NCBI | |
Taheri SA, Yeh J, Batt RE, Fang Y, Ashraf H, Heffner R, Nemes B and Naughton J: Uterine myometrium as a cell patch as an alternative graft for transplantation to infarcted cardiac myocardium: A preliminary study. Int J Artif Organs. 31:62–67. 2008. View Article : Google Scholar : PubMed/NCBI | |
Wei X, Chang ACH, Chang H, Xu S, Xue Y, Zhang Y, Lei M, Chang ACY and Zhang Q: Hypoglycemia-exacerbated mitochondrial connexin 43 accumulation aggravates cardiac dysfunction in diabetic cardiomyopathy. Front Cardiovasc Med. 9:8001852022. View Article : Google Scholar : PubMed/NCBI | |
Marsh SR, Williams ZJ, Pridham KJ and Gourdie RG: Peptidic connexin43 therapeutics in cardiac reparative medicine. J Cardiovasc Dev. 8:522021. | |
Shao Q, Esseltine JL, Huang T, Novielli-Kuntz N, Ching JE, Sampson J and Laird DW: Connexin43 is dispensable for early stage human mesenchymal stem cell adipogenic differentiation but is protective against cell senescence. Biomolecules. 9:4742019. View Article : Google Scholar : | |
Liu C, Fan Y, Zhou L, Zhu HY, Song YC, Hu L, Wang Y and Li QP: Pretreatment of mesenchymal stem cells with angiotensin II enhances paracrine effects, angiogenesis, gap junction formation and therapeutic efficacy for myocardial infarction. Int J Cardiol. 188:22–32. 2015. View Article : Google Scholar : PubMed/NCBI | |
Zhou Y, Zhang YX, Yang KL, Liu YL, Wu FH, Gao YR and Liu W: Connexin 43 mediated the angiogenesis of buyang huanwu decoction via vascular endothelial growth factor and angiopoietin-1 after ischemic stroke. Chin J Physiol. 65:72–79. 2022. View Article : Google Scholar : PubMed/NCBI | |
Das H, George JC, Joseph M, Das M, Abdulhameed N, Blitz A, Khan M, Sakthivel R, Mao HQ, Hoit BD, et al: Stem cell therapy with overexpressed VEGF and PDGF genes improves cardiac function in a rat infarct model. PLoS One. 4:e73252009. View Article : Google Scholar : PubMed/NCBI |