Open Access

Connexins and angiogenesis: Functional aspects, pathogenesis, and emerging therapies (Review)

  • Authors:
    • Zizi Zhou
    • Wenxiang Chai
    • Yi Liu
    • Meng Zhou
    • Xiaoming Zhang
  • View Affiliations

  • 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.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )


Abstract

Connexins (Cxs) play key roles in cellular communication. By facilitating metabolite exchange or interfering with distinct signaling pathways, Cxs affect cell homeostasis, proliferation, and differentiation. Variations in the activity and expression of Cxs have been linked to numerous clinical conditions including carcinomas, cardiac disorders, and wound healing. Recent discoveries on the association between Cxs and angiogenesis have sparked interest in Cx‑mediated angiogenesis due to its essential functions in tissue formation, wound repair, tumor growth, and metastasis. It is now widely recognized that understanding the association between Cxs and angiogenesis may aid in the development of new targeted therapies for angiogenic diseases. The aim of the present review was to provide a comprehensive overview of Cxs and Cx‑mediated angiogenesis, with a focus on therapeutic implications.

1. Introduction

Angiogenesis plays a significant role in tissue growth, wound repair, tumor development, and metastasis. It is controlled by growth factors, pro-angiogenic cytokines, and neovascularization antagonists (1). Connexins (Cxs) are hexameric arrays of tetraspan integral membrane proteins that form gap junctions (GJs). GJs provide direct ionic and molecular communication between neighboring cells and coordinate the exchange of chemicals and electrical impulses between them.

Several studies have reported independent and GJ-dependent roles of Cxs in mediating angiogenesis in various disorders (2,3). Although there are a few reviews on the role of Cxs in various physiological processes (4-9), there is little discussion of how Cxs influence the angiogenic process involved in wound repair, tumorigeneses, and cardiovascular disorders. The purpose of the present study was to examine the current state of knowledge regarding Cx structure, nomenclature, function, and regulation, as well as the newly identified link between Cxs and angiogenesis. Major Cx-mediated angio- genesis disorders and potential therapeutic approaches were also examined.

2. Methodology

A literature search was performed to identify articles that discussed the role of connexins in angiogenesis. The MEDLINE, PubMed, Scopus, and Cochrane Library databases were searched until June 02, 2022. Individual or combined searches for the terms 'angiogenesis', 'connexin', 'Cx', and 'gap junctions' were performed. By scanning the references of the included studies, additional studies were identified. Letters to the editor and articles without abstracts were excluded.

Structure and diversity of Cxs and GJs

Each Cx has four hydrophobic transmembranes (M1-M4), two extracellular areas (E1 and E2) that bind to another Cx in the neighboring cell, and three cytoplasmic regions that correspond to the cytoplasmic loop (CL), and the amino-terminal (NT), and carboxy-terminal (CT) tail regions. The N-terminus, membrane-spanning sections, and extracellular loops are consistent throughout the structure; however, the size and structure of the CL and the CT are not. The GJ channel is composed of two hemichannels (or connexons), consisting of six transmembrane proteins (Cx subunits) connected to the plasma membrane of each symmetric cell. When two hemichannels join to produce a cell-cell conduit, one is tilted by 30° with respect to the other. Homotypic GJs are formed when identical Cx subunits dock, whereas heterotypic GJs are formed when two different connexons (hemichannels) dock (10). The central cytoplasmic part and the second extracellular domain (E2) regulate the heterotypic adaptation of Cxs. Heterotypic channels have features that differ from those of homotypic channels, such as unitary conductance and gating. The permeabilities of different channels formed by different Cxs differ, allowing secondary messengers to be discriminated against (cyclic guanosine monophosphate, Ca2+, or IP3) (Fig. 1).

Functional role of Cxs

Hemichannels regulate cellular responses to a wide range of physiological, oxidative, and metabolic stressors, whereas GJs permit intercellular trans- mission (Fig. 1). Molecules transported through these channels are responsible for several physiological functions. Different stimuli, including variations in voltage, Ca2+, pH, and Cx phosphorylation, can dynamically control gap junctional intercellular communication (GJIC) (10-15). Voltage sensitivity is critical for controlling the intercellular connectivity of excitable cells. Channel independence has been demonstrated in the context of cellular proliferation, attachment, motility, apoptotic processes, and signaling (2,12,16-19). It was also recently revealed by the authors' research group that Cx43 levels regulate angiogenesis in endothelial cells (ECs), irrespective of GJ function (2). Moorby and Patel conducted extensive research on the GJ-dependent and-independent functions of Cx43 and discovered that the carboxyl region of Cx43 mainly governs the independent GJ function (19). It is increasingly accepted that the effects of GJIC-independent Cxs on carcinogenesis extend beyond proliferation and migration, including angiogenesis and cell death (20-23).

Cxs and angiogenic processes

Angiogenesis plays a crucial role in tissue growth, wound healing (WH), carcinogenesis, and metastasis (1,24). It begins with the growth and development of preexisting vessels, depending on a mixture of growth factors and proangiogenic cytokines, and is regulated by various neovascularization antagonists (Fig. 2) (25,26). Cxs have been shown to affect angiogenic processes in various ways, including growth, transport, and cellular stiffness (27). The roles of Cx43, Cx37, and Cx40, which are the most prevalent Cxs engaged in angiogenic processes, are discussed in the next section. The expression of Cx43 expression influences the angiogenic potential of endothelial cells independently of the GJ interaction. Because proliferation was unchanged, it was hypothesized that the Cx43 protein may significantly alter endothelial cell relocation, thereby promoting angiogenesis (2).

Cx43

Decreased Cx43 expression can result in vascular dysfunction and impaired angiogenesis (28). Cx43 is also involved in regulating lung microvascular permeability, and its modulation is related to endothelial monolayer permeability (29,30). Salmina et al examined GJ-dependent neurogenesis and concluded that alterations in Cx43 expression were correlated with distinct steps in neural growth (31). Cx43 is also upregulated in ECs during hemodynamic stimulation-induced angiogenesis (32). A study of the molecular processes during human trophoblast fusion revealed that protein kinase A-dependent phosphorylation of Cx43 enhances cell fusion (33). Furthermore, decreased Cx43 expression can result in improper embryo implantation and inadequate angiogenesis (34). It has also been found that Cx43, as a negative regulator, participates in critical steps of WH, such as inflammation response, remodeling of the extracellular matrix, proliferation of epidermal/skin cells, and migration (35).

Cx37 and Cx40

Cx37 and Cx40, which are co-expressed in ECs, have overlapping functions. Cx40 can promote EC migration, vessel sprouting, and expansion, whereas Cx40 deficiency and inhibition reduce angiogenesis (36). Endothelial Cx40, according to Haefliger et al, affects the initial phases of angiogenesis in the retina by controlling vascularization (37). In Cx37−/− mice, improved recovery of the hind limb was associated with increased vasculogenesis, which resulted in greater collateral remodeling and angiogenesis (38). Furthermore, the global deletion of Cx37 in mice causes increased angiogenesis during tissue injury, aiding the recovery process after ischemic injury (39). Growth inhibition mediated by Cx37 involves CT and the pore-forming domain (14). Nitric oxide affects endothelial vasomotor activity by modulating calcium signaling (40). Cx37 and Cx40 have been shown to uniquely control post-ischemic limb perfusion, affecting the intensity of ischemic stress and, as a result, post-ischemic persistence (41). Cx37 selectively affects Ang II signaling by modulating Ang II receptor expression (42). Cx37 also suppresses the proliferation of vascular and cancer cells. Cx37-induced growth arrest or growth-permissive phenotypes depend on conformational changes in Cx37 caused by phosphorylation (43).

3. Cxs, diseases and potential therapies

Cxs are implicated in the regulation of innate epithelial immunity, wound repair, and inflammatory processes. The pathophysiology of various Cx-related diseases is determined by both the canonical and noncanonical functions of Cxs. Given the presence of several Cxs in the endothelium, it is possible that Cxs and immune-targeted therapies could be used synergistically. In various pathological conditions, such as ischemia, optic nerve damage, stroke, and spinal cord injury, communication between junctions and hemichannels leads to secondary damage through inflammatory processes (44). Cx43 enhanced brain blood flow restoration in a mouse model by regulating reparative angiogenesis during chronic cerebral hypoperfusion (45). Due to the variety of Cx-mediated communication and its effect on cellular physiology and pathology, a definitive link between Cxs, angiogenesis, and disease has not yet been identified. However, in numerous cases, an association between aberrant Cx function, angiogenesis, and disease has been observed. The following section highlights the key mechanistic and therapeutic findings.

WH

Different layers of the human epidermis express different levels of Cxs, which are associated with a number of skin diseases (Fig. 3). During the early phases of WH, Cx43 has been observed to be negatively regulated at the wound margins (46). Nitric oxide, a mediator of vasomotion, has been reported to be a strong modulator of GJ coupling in ECs (47). It promotes the de novo formation of GJ by expanding the integration of Cx40 into the plasma membrane. One of the most evident applications that demonstrates the involvement of Cxs in angiogenesis is the efficacy of bioactive glass (BG) in WH. In rats, BG stimulates GJIC, which results in increased angiogenesis and accelerates the closure of excisional wounds (48). It was recently shown that BG affects the expression of Cx43 and ROS levels, increasing WH by suppressing pyroptosis through the Cx43/ROS signaling pathway (49). Cx43 remodeling is an important event in WH that influences the cellular dynamics of keratinocytes and fibroblasts (50). It was revealed that siRNA knockdown of Cx43 in human microvascular endothelial cells reduced migration in vitro, as measured by a wound assay, and impaired aortic vessel sprouting ex vivo (16); Cx43 and the tyrosine phosphatase, SHP-2, were also revealed to mediate endothelial cell migration, revealing a novel interaction between Cx43 and SHP-2 that is required for this process (16).

Mutations in Cx26, Cx30, and Cx31 are associated with hyperproliferative skin diseases (51). Furthermore, suppression of Cx43 function affects the expression of genes associated with WH (52). Cx mutations are associated with epidermal dysplasia (15). Gain-of-function mutations alter Cx-mediated calcium signaling within the epidermis; for example, suppressing Cx43 activity in fibroblasts has been shown to increase migration and control the expression of genes associated with WH through the mitogen-activated protein kinase, specificity protein 1, activator protein 1, glycogen synthase kinase 3, and transforming growth factor pathways, contributing to rapid and scarless WH in the human gingiva (52).

Preclinical studies on peptide therapeutics, a mimetic of Cx43 CT, have reported improvements in WH (53). Cx43 has also been reported to counter-regulate caveolin-1 in controlling EC proliferation and migration, and this counterregulatory effect of Cx43 could be used in therapeutic angiogenesis (54). Morphine administration was found to inhibit angiogenesis and delay WH by upregulating Cx43, and high doses of morphine alter Cx43 expression by increasing fibronectin and actin levels through the activation of transforming growth factor signaling (55). A Cx43 mimetic peptide (TAT-Gap19) significantly upregulates matrix metalloproteinases, tenascin-C, and vascular endothelial growth factor (VEGF)-A (13).

Cancer

In cancer cells, intercellular communication is aberrant, and numerous studies have suggested that dysfunctional GJ and Cxs play a key role in this process (56). However, there appears to be a skewed association between Cxs and cancer, with evidence suggesting that Cxs may limit cancer cell development in certain instances while also promoting cancer cell motility, invasion, and metastatic dissemination in others (57,58). A key study revealed that inhibiting Cx37 decreases tumor angiogenesis; moreover, Cx37 and Cx40 work together to promote tumorigenesis (20). Consequently, the involvement of Cxs and GJs in cancer is more complex than previously thought.

Breast tumor cells transplanted into heterozygous Cx43 mice did not affect tumor growth, but greatly improved vascularization, indicating the role of Cx43 in vessel quiescence control and pathological tumor angiogenesis (22). The passage of tumor cells through the endothelial barrier is an important step in metastasis, in which endothelial cells adhere to the target organ by direct cell-cell communication and paracrine activation to initiate angiogenesis (Fig. 4). Cx46 regulates cancer stem cell and epithelial-to-mesenchymal transition features in breast cancer cells, suggesting that it may be useful in the development of future cancer therapeutics (59).

Intercellular communication is also required for tumor cell trafficking across the lymphatic endothelium (60). Hemichannels have been reported to facilitate interactions between cancer cells and blood vessels, leading to angiogenesis. Choudhary et al revealed that tumors downregulate Cx43 function, allowing the endothelium to respond to angiogenic stimuli, leading to pathogenic angiogenesis (22). The roles of Cx and Notch endothelial signaling in coordinating the appropriate proliferation and angiogenesis of ECs have been identified (61). It has also been shown that GJIC inhibits tumor growth by transferring microRNAs from one EC to surrounding tumor cells, indicating a bystander role that can be exploited in cancer treatment (21).

Targeting Cx may be a promising therapeutic approach for cancer (23). Exosomes containing anti-angiogenic microRNAs released immediately through Cx channels can prevent cancer cells from promoting angiogenesis (21). Peptide-mediated inhibition of Cx40 in EC is a successful anti-angiogenesis approach that suppresses tumor angiogenesis (36). In the conditioned medium, tumor size and vessel density in Cx43-knockdown tumor cells decreased, indicating that Cx43 prevented tumor growth by decreasing angiogenesis (62).

Cardiovascular disorders

Several Cxs are co-expressed in the heart; in particular, distinct combinations of Cx40, Cx43, and Cx45 are observed in functionally specialized cardiomyocytes (Fig. 5). GJ channels in the cardiovascular system regulate vascular tone, which is essential for the coordination of cell activity, by permitting the transport of chemical messengers and energy substrates (63-65). Cxs form GJs for the transmission of precisely choreographed current flow patterns that control the synchronized beat of a healthy heart. Several pathophysiological conditions, including atherosclerosis, hypertension, hypertrophy, ischemia, and arrhythmias, have been linked to dysregulation of Cxs in the cardiovascular system in terms of expression, function, posttranslational modifications, and location. Ugwu et al reported a recurring somatic Cx43-gene c.121G>T mutation as a cause of cutaneous venous abnormalities (66). Although Cx43 levels are high in cardiac neural crest cells, both heterozygous and homozygous knock-in mice live long and do not exhibit symptoms of coronary heart disease (67). Similarly, point mutations in Cx43 were not found to cause the tetralogy of Fallot (68).

Treatment with granulocyte colony-stimulating factor improves arterial and capillary density and increases Cx43 expression in failing hearts (69). Through Cx43, VEGF stimulates endothelial progenitor cells and supports vascular healing (70). In ECs, ischemia/reperfusion causes reactive species to disrupt Cx/pannexin signaling mitochondrial prompt division and promote macrovesicle release (71). Cx43 and angiogenesis levels are higher in the exercised mouse heart, indicating increased remodeling (72). Long-term alienation combined with moderate environmental pressure has been associated with depressive symptoms and aberrant expression of Cx43 and Cx45 in the left ventricle (73). Notably, EC-specific molecule 1 enhances the potential of induced pluripotent stem ECs to promote angiogenesis and neovascularization (74). Su et al determined that preconditioning for ischemia had cardioprotective effects on arrhythmia and myocardial recovery by upregulating phosphatidylinositol 3-kinase-mediated Cx43 signaling (75). In a study on myometrial cell patch transplantation to cure myocardial infarction, angiogenesis was reported to occur in the trans- planted myometrium and Cx43 expression was observed in the transplanted patches (76). Cx43 passivation from intercellular signaling and buildup at the mitochondrial inner membrane has been revealed in diabetic cardiomyocytes, demonstrating that mtCx43 is responsible for triggering aberrant contraction and disrupting electrophysiology in cardiomyocytes (77).

Heart disease caused by myocardial tissue injury and fibrosis is related to Cx43-based GJs. As a result, several Cx43 mimetic peptides have been proposed as potential therapeutics for Cx43-related degenerative disorders, some even reaching human clinical trials (78). Cx43 improves infarcted heart angiogenesis, as evidenced by higher levels of VEGF and basic fibroblast growth factor (18). The cardioprotective properties of expanded umbilical cord mesenchymal stem cells (MSC) were attributed to paracrine substances that tend to enhance angiogenesis and preserve Cx43 GJ function (75). Cx43 was found to be dispensable for the adipogenic differentiation of early-stage MSC, although it was protective against cell senescence (79). The survival and tube formation of MSCs are improved by Ang II treatment and Cx43 expression (80). TEM immunogold studies on rat heart ventricles indicated the lack of Cx26 at intercalated discs but the presence of Cx26 at various subcellular compartments (17). It was found that after a localized ischemic stroke, Cx43 regulated the angiogenesis of Buyang Huanwu decoction through VEGF and Ang-1 (81). Due to the increase of tissue Cx43 and proangiogenic markers, regenerative treatment using nanofiber-expanded hematopoietic stem cells has been reported to have a favorable effect on rat heart function following myocardial infarction (82).

4. Conclusions and future directions

Several studies have elucidated GJ/Cx-mediated angiogenesis. To adequately describe the de novo blood vessels involved in the response to tumor angiogenesis, researchers must examine changes in the expression patterns of GJIC and Cxs in pro-angiogenic stimuli in the neovasculature. Antiangiogenic therapy has been shown to increase survival in human tumors; therefore, GJ-and Cx-targeting techniques could be useful in the development of novel medicines. Chemical blockers of Cx channels, peptide mimics of short Cx sequences, such as Gap19/24/27/40, and gene therapy techniques have all been shown to be extremely effective molecular techniques for unraveling the complexity of the function of Cxs. Future research should focus on determining the specific molecular pathways underlying the significance of Cxs in various diseases and designing randomized control trials for specific therapeutic alternatives.

Availability of data and materials

Not applicable.

Authors' contributions

ZZ, WC, YL and MZ contributed to the study concept, design, literature search and computer graphics for the figures. ZZ wrote the manuscript. XZ revised the manuscript and was in charge of the final approval of the manuscript prior to submission. Data authentication is not applicable. All authors read and approved the final manuscript and agree to be accountable for all aspects of the research in ensuring that the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Ethics approval and consent to participate

Not applicable.

Patient consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Acknowledgments

Not applicable.

Funding

The present study was funded by the Natural Science Foundation of Shenzhen University General Hospital (grant no. SUGH2019QD007 to ZZ; grant no. SUGH2019QD014 to XZ) and the Science and Technology Foundation of Nanshan District, Shenzhen (grant no. NS2021167 to ZZ). The funding provided financial support for the data collection, the analysis of the collected data and computer graphics.

Abbreviations:

BG

bioactive glass

CL

cytoplasmic loop

CT

carboxy-terminal

ECs

endothelial cells

GJ

gap junctions

GJIC

Gap junctional intercellular communication

MSC

mesenchymal stem cells

VEGF

vascular endothelial growth factor

WH

wound healing

References

1 

Carmeliet P: Mechanisms of angiogenesis and arteriogenesis. Nat Med. 6:389–395. 2000. View Article : Google Scholar : PubMed/NCBI

2 

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

3 

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

4 

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

5 

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

6 

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

7 

Laird DW and Lampe PD: Cellular mechanisms of connexin-based inherited diseases. Trends Cell Biol. 32:58–69. 2022. View Article : Google Scholar

8 

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

9 

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

10 

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

11 

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

12 

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

13 

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

14 

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

15 

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

16 

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

17 

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

18 

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

19 

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

20 

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

21 

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

22 

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

23 

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

24 

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

25 

Polverini PJ: The pathophysiology of angiogenesis. Crit Rev Oral Biol Med. 6:230–247. 1995. View Article : Google Scholar : PubMed/NCBI

26 

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

27 

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 :

28 

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

29 

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

30 

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

31 

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

32 

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

33 

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

34 

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

35 

Zhang XF and Cui X: Connexin 43: Key roles in the skin. Biomed Rep. 6:605–611. 2017. View Article : Google Scholar : PubMed/NCBI

36 

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

37 

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

38 

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

39 

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

40 

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

41 

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

42 

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

43 

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

44 

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

45 

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

46 

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

47 

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

48 

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

49 

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

50 

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 :

51 

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

52 

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

53 

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 :

54 

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

55 

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

56 

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

57 

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

58 

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 :

59 

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

60 

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

61 

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

62 

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

63 

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

64 

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

65 

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

66 

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.

67 

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

68 

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

69 

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

70 

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

71 

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

72 

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

73 

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 :

74 

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

75 

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

76 

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

77 

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

78 

Marsh SR, Williams ZJ, Pridham KJ and Gourdie RG: Peptidic connexin43 therapeutics in cardiac reparative medicine. J Cardiovasc Dev. 8:522021.

79 

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 :

80 

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

81 

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

82 

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

Related Articles

Journal Cover

August-2022
Volume 50 Issue 2

Print ISSN: 1107-3756
Online ISSN:1791-244X

Sign up for eToc alerts

Recommend to Library

Copy and paste a formatted citation
x
Spandidos Publications style
Zhou Z, Chai W, Liu Y, Zhou M and Zhang X: Connexins and angiogenesis: Functional aspects, pathogenesis, and emerging therapies (Review). Int J Mol Med 50: 110, 2022
APA
Zhou, Z., Chai, W., Liu, Y., Zhou, M., & Zhang, X. (2022). Connexins and angiogenesis: Functional aspects, pathogenesis, and emerging therapies (Review). International Journal of Molecular Medicine, 50, 110. https://doi.org/10.3892/ijmm.2022.5166
MLA
Zhou, Z., Chai, W., Liu, Y., Zhou, M., Zhang, X."Connexins and angiogenesis: Functional aspects, pathogenesis, and emerging therapies (Review)". International Journal of Molecular Medicine 50.2 (2022): 110.
Chicago
Zhou, Z., Chai, W., Liu, Y., Zhou, M., Zhang, X."Connexins and angiogenesis: Functional aspects, pathogenesis, and emerging therapies (Review)". International Journal of Molecular Medicine 50, no. 2 (2022): 110. https://doi.org/10.3892/ijmm.2022.5166