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Connexome-Associated Pathways in Atherosclerosis: History
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Contributor: Michelle Giovanna Santoyo Suárez , Adriana G Quiroz-Reyes , Mayela del Angel Martinez , Gabriel Garcia-Gonzalez , Paulina Delgado-Gonzalez , Elsa Garza-Treviño , Gerardo Padilla-Rivas , Jose Francisco Islas

The connexome comprises the network of intercellular communication structures formed by connexins, pannexins, and associated regulatory proteins within the vasculature. These channels enable the exchange of ions, metabolites, and signaling molecules between endothelial cells, vascular smooth muscle cells, immune cells, and fibroblasts. In healthy vessels, the connexome maintains endothelial quiescence, shear stress responsiveness, and coordinated vascular homeostasis. In atherosclerosis, disturbed flow, inflammation, and oxidative stress remodel connexome composition—most notably through increased Cx43 expression, reduced Cx37/Cx40 activity, and enhanced Panx1-mediated ATP release. These alterations promote endothelial activation, leukocyte recruitment, smooth muscle proliferation, and inflammasome signaling, positioning the connexome as a central regulator of vascular dysfunction and plaque progression.

  • connexome
  • krupple-like factors

Connexome-Associated Pathways in Atherosclerosis

Overview

The connexome refers to the coordinated network of connexins (Cx), pannexins (Panx), gap junctions (GJ), hemichannels, and interacting proteins that mediate electrical, metabolic, and paracrine communication among the vascular cells. This communication is essential for maintaining endothelial integrity, vascular tone, inflammatory balance, and smooth muscle phenotype. Unfortunetlly, the development of atherosclerosis profoundly disturbs these communication systems, leading to endothelial dysfunction, leukocyte recruitment, maladaptive smooth muscle remodeling, chronic inflammation, and ultimately plaque destabilization[1][2][3]. Regions of disturbed flow exhibit marked upregulation of pro-atherogenic connexins—particularly connexin 43 (Cx43)—which amplifies ATP release, immune activation, and endothelial permeability[4][5][6][7].

Connexome Components

Connexins form hexameric hemichannels that pair to create gap junctions enabling direct cytoplasmic component exchange. Amongst these connexins, Connexin 37 (Cx37) is enriched in the arterial endothelium and plays a protective role by limiting monocyte adhesion and supporting endothelial quiescence[5][8]. Connexin 40 (Cx40) promotes nitric oxide production, maintains anti-inflammatory signaling, and supports vascular homeostasis[8][9]. In contrast, connexin 43 (Cx43) is strongly induced under oscillatory shear stress and inflammatory conditions[4][5][7], where it promotes leukocyte adhesion, macrophage infiltration, foam cell formation, and smooth muscle migration[10][11]. Connexin 45 (Cx45) participates in vascular development and smooth muscle electrical communication[12].

On the other hand, Pannexins and particular Pannexin 1 (Panx1) functions predominantly as a mechanosensitive ATP-release channel activated by cytokines, oxidative stress, and mechanical strain[13][14]. Panx1-mediated ATP release triggers purinergic P2X7 receptor activation, K+ efflux, and NLRP3 inflammasome assembly, causing pyroptosis and accumulation of debris, hence escalating inflammatory signaling in atherosclerosis[13][15].

Connexome Remodeling in Atherosclerosis

Atherosclerotic lesions preferentially develop in arterial branches or curvatures where blood flow is disturbed. Here, endothelial cells can lose their protective flow-dependent transcriptional programs and move toward an inflammatory phenotype characterized by the reduction of both KLF2 and KLF4 expression[8][9][16]. This shift decreases the protective expression of both Cx37 and Cx40[5][8] and increases the expression and phosphorylation of Cx43[4][10][7].

Enhanced ATP release through bith Cx43 and Panx1 amplifies endothelial activation and leukocyte recruitment[13][14][15]. Smooth muscle cells respond to increased Cx43 signaling by adopting a synthetic, proliferative phenotype conducive to neointimal growth[10][11].

Panx1-dependent ATP release activates the NLRP3 inflammasome, leading to secuential caspase-1 activation and IL-1β secretion, processes that contribute to necrotic core expansion and plaque vulnerability[13][15][17].

Regulatory Pathways Governing the Connexome

1. The KLF2/KLF4 Shear-Stress Axis

Laminar shear stress activates the MEKK2–MEK5–ERK5 pathway, stimulating MEF2 and resulting in the upregulation of both KLF2 and KLF4[8][9][16]. These transcription factors enhance expression of both Cx37 and Cx40[5][8] while suppressing Cx43[4][7]. Loss of the KLF2/KLF4 signaling under disturbed flow fosters endothelial inflammation and connexome dysregulation.

2. NF-κB Pathway

Inflammatory cytokines including TNF-α and IL-1β can help activate NF-κB signaling, which in turn increases Cx43 transcription and drives phosphorylation patterns favoring hemichannel opening[4][7][18]. This promotes endothelial activation, barrier dysfunction, and leukocyte recruitment[1][3].

3. MAPK Pathways

ERK, JNK, and p38 MAPKs modify the overall connexin behavior through transcriptional and post-translational mechanisms. First, ERK promotes Cx43 internalization and turnover[18], then JNK elevates Cx43 expression during oxidative stress[11], and finally p38 increases hemichannel opening and inflammatory coupling[15].

4. PI3K–Akt/eNOS Signaling

Akt signaling promotes endothelial homeostasis and supports Cx40 expression (28). Reduced nitric oxide bioavailability, a common condition in atherosclerosis enhances Cx43 hemichannel opening and promotes endothelial dysfunction[12].

5. Notch Signaling

Laminar shear stimulates Notch1–RBPJ signaling, which in turn suppresses Cx43 expression and maintains endothelial quiescence[16]. Meanwhile the loss of Notch activity in disturbed flow promotes endothelial-mesenchymal transition and enhances vascular inflammation[10].

6. TGF-β/SMAD Pathway

TGF-β signaling induces Cx43 through the activation of SMAD2/3[18][11]. Crosstalk with RhoA/ROCK and YAP/TAZ mechanotransduction pathways intensifies cytoskeletal tension, enhances matrix remodeling, and promotes connexin trafficking[19][20].

7. Oxidative Stress & Nrf2

Reactive oxygen species oxidize Cx43 and Panx1, increasing hemichannel activity and weakening endothelial integrity[15]. Nontheless, Nrf2 activation counters these effects by restoring antioxidant defenses and supporting Cx37 and Cx40 expression[14]. However, Nrf2 is often suppressed in plaques[15].

8. NLRP3 Inflammasome Activation

Panx1-mediated ATP release activates P2X7 and the NLRP3 inflammasome[13][15]. This leads to caspase-1 activation and IL-1β maturation, both key contributors to plaque expansion and inflammation[21][17].

9. RhoA/ROCK Mechanotransduction

RhoA/ROCK enhances actomyosin tension and increases the trafficking of Cx43 to the plasma membrane under disturbed flow, promoting inflammatory remodeling[19].

10. YAP/TAZ Mechanotransduction

YAP and TAZ both respond to changes in matrix stiffness and oscillatory shear by entering the nucleus and increasing Cx43 transcription. This activation promotes smooth muscle proliferation and migration, thereby contributing to the overall plaque progression[13].

Nanomedicine and Therapeutic Modulation of the Connexome

Nanotechnology offers new tools for imaging, modulating, and repairing connexome signaling, which is a potentially crucial step in mitigating the developmemnt, as well as the effects of atherosclerosis. Targeted nanoparticles that bind VCAM-1, ICAM-1, macrophages, or oxidized lipids provide highly sensitive plaque imaging[22][23][24]. Therapeutic delivery systems—including siRNA, miRNA mimics/inhibitors, and mRNA nanoparticles—are being developed to restore KLF2/KLF4 signaling or suppress Cx43 and Panx1 activation[25][21]. Connexin-modulating peptides such as Gap26, Gap27, and TAT-Gap19 can selectively inhibit Cx43 hemichannels when delivered via nanoparticles[26]. Multifunctional theranostic platforms combine real-time imaging with connexome-targeted therapy[17][20][27].  

Future Directions

Emerging technologies—including single-cell transcriptomics, spatial proteomics, and computational flow modeling—are revealing cell-specific patterns of connexome regulation in unprecedented detail[16]. The integration of mechanobiology, inflammation, and nanotherapeutics is guiding next-generation strategies aimed at normalizing Cx37, Cx40, Cx43, and Panx1 activity. Precision modulation of the connexome signaling is increasingly seen as a promising approach for the stabilizing of plaques and reducing the burden of atherosclerotic cardiovascular disease [17][20][27].

This entry is adapted from: 10.1080/17435889.2025.2587712

References

  1. Ira Tabas; Andrew H. Lichtman; Monocyte-Macrophages and T Cells in Atherosclerosis. Immun. 2017, 47, 621-634, .
  2. Shifa Jebari-Benslaiman; Unai Galicia-García; Asier Larrea-Sebal; Javier Rekondo Olaetxea; Iraide Alloza; Koen Vandenbroeck; Asier Benito-Vicente; César Martín; Pathophysiology of Atherosclerosis. Int. J. Mol. Sci. 2022, 23, 3346, .
  3. Leah I. Susser; Katey J. Rayner; Through the layers: how macrophages drive atherosclerosis across the vessel wall. J. Clin. Investig. 2022, 132, e157011, .
  4. Anna Pfenniger; Marc Chanson; Brenda R. Kwak; Connexins in atherosclerosis. Biochim. et Biophys. Acta (BBA) - Biomembr. 2013, 1828, 157-166, .
  5. Merlijn J. Meens; Anna Pfenniger; Brenda R. Kwak; Mario Delmar; Regulation of cardiovascular connexins by mechanical forces and junctions. Cardiovasc. Res. 2013, 99, 304-314, .
  6. Su Tu; Fu-Tao Cao; Xiao-Chun Fan; Cheng-Jian Yang; Resveratrol protects the loss of connexin 43 induced by ethanol exposure in neonatal mouse cardiomyocytes. Naunyn-Schmiedeberg's Arch. Pharmacol. 2017, 390, 651-660, .
  7. Chen Yuan Kam; Adi D. Dubash; Elisa Magistrati; Simona Polo; Karla J.F. Satchell; Farah Sheikh; Paul D. Lampe; Kathleen J. Green; Desmoplakin maintains gap junctions by inhibiting Ras/MAPK and lysosomal degradation of connexin-43. J. Cell Biol. 2018, 217, 3219-3235, .
  8. Reinier A. Boon; Joost O. Fledderus; Oscar L. Volger; Eva J.A. van Wanrooij; Evangelia Pardali; Frank Weesie; Johan Kuiper; Hans Pannekoek; Peter Ten Dijke; Anton J.G. Horrevoets; et al. KLF2 Suppresses TGF-β Signaling in Endothelium Through Induction of Smad7 and Inhibition of AP-1. Arter. Thromb. Vasc. Biol. 2007, 27, 532-539, .
  9. Joost O. Fledderus; Reinier A. Boon; Oscar L. Volger; Hanna Hurttila; Seppo Ylä-Herttuala; Hans Pannekoek; Anna-Liisa Levonen; Anton J.G. Horrevoets; KLF2 Primes the Antioxidant Transcription Factor Nrf2 for Activation in Endothelial Cells. Arter. Thromb. Vasc. Biol. 2008, 28, 1339-1346, .
  10. Mónica Márquez; Matías Muñoz; Alexandra Córdova; Mariela Puebla; Xavier F. Figueroa; Connexin 40-Mediated Regulation of Systemic Circulation and Arterial Blood Pressure. J. Vasc. Res. 2023, 60, 87-100, .
  11. Haojie Yang; Xixiang Xi; Bin Zhao; Zhenxi Su; Zhenyi Wang; KLF4 protects brain microvascular endothelial cells from ischemic stroke induced apoptosis by transcriptionally activating MALAT1. Biochem. Biophys. Res. Commun. 2018, 495, 2376-2382, .
  12. Michael J. Davis; Scott Earley; Yi-Shuan Li; Shu Chien; Vascular mechanotransduction. Physiol. Rev. 2023, 103, 1247-1421, .
  13. Hailong Yu; Xiang Cao; Wei Li; Pinyi Liu; Yuanyuan Zhao; Lilong Song; Jian Chen; Beilei Chen; Wenkui Yu; Yun Xu; et al. Targeting connexin 43 provides anti-inflammatory effects after intracerebral hemorrhage injury by regulating YAP signaling. J. Neuroinflammation 2020, 17, 1-19, .
  14. Olga M. Rusiecka; Jade Montgomery; Sandrine Morel; Daniela Batista-Almeida; Raf Van Campenhout; Mathieu Vinken; Henrique Girao; Brenda R. Kwak; Canonical and Non-Canonical Roles of Connexin43 in Cardioprotection. Biomol. 2020, 10, 1225, .
  15. Siarhei A. Dabravolski; Vasily N. Sukhorukov; Vladislav A. Kalmykov; Andrey V. Grechko; Nikolay K. Shakhpazyan; Alexander N. Orekhov; The Role of KLF2 in the Regulation of Atherosclerosis Development and Potential Use of KLF2-Targeted Therapy. Biomed. 2022, 10, 254, .
  16. Peter F. Davies; Mete Civelek; Yun Fang; Ingrid Fleming; The atherosusceptible endothelium: endothelial phenotypes in complex haemodynamic shear stress regions in vivo. Cardiovasc. Res. 2013, 99, 315-327, .
  17. Fei Yan; Yu Sun; Yang Mao; Meiying Wu; Zhiting Deng; Shuai Li; Xin Liu; Li Xue; Hairong Zheng; Ultrasound Molecular Imaging of Atherosclerosis for Early Diagnosis and Therapeutic Evaluation through Leucocyte-like Multiple Targeted Microbubbles. Theranostics 2018, 8, 1879-1891, .
  18. Erika Geimonen; Wei Jiang; Mariam Ali; Glenn I. Fishman; Robert E. Garfield; Janet Andersen; Activation of Protein Kinase C in Human Uterine Smooth Muscle Induces connexin-43 Gene Transcription through an AP-1 Site in the Promoter Sequence. J. Biol. Chem. 1996, 271, 23667-23674, .
  19. Takayuki Okamoto; Eun Jeong Park; Eiji Kawamoto; Haruki Usuda; Koichiro Wada; Akihiko Taguchi; Motomu Shimaoka; Endothelial connexin-integrin crosstalk in vascular inflammation. Biochim. et Biophys. Acta (BBA) - Mol. Basis Dis. 2021, 1867, 166168, .
  20. Binura Perera; Yuao Wu; Nam-Trung Nguyen; Hang Thu Ta; Advances in drug delivery to atherosclerosis: Investigating the efficiency of different nanomaterials employed for different type of drugs. Mater. Today Bio 2023, 22, 100767, .
  21. Mukesh Punjabi; Lifen Xu; Amanda Ochoa-Espinosa; Alexandra Kosareva; Thomas Wolff; Ahmed Murtaja; Alexis Broisat; Nick Devoogdt; Beat A. Kaufmann; Ultrasound Molecular Imaging of Atherosclerosis With Nanobodies. Arter. Thromb. Vasc. Biol. 2019, 39, 2520-2530, .
  22. Matthias Nahrendorf; Edmund Keliher; Peter Panizzi; Hanwen Zhang; Sheena Hembrador; Jose-Luiz Figueiredo; Elena Aikawa; Kimberly Kelly; Peter Libby; Ralph Weissleder; et al. 18F-4V for PET–CT Imaging of VCAM-1 Expression in Atherosclerosis. JACC: Cardiovasc. Imaging 2009, 2, 1213-1222, .
  23. Ashwath Jayagopal; Yan Ru Su; John L Blakemore; MacRae F Linton; Sergio Fazio; Frederick R Haselton; Quantum dot mediated imaging of atherosclerosis. Nanotechnol. 2009, 20, 165102-165102, .
  24. Max L. Senders; Sophie Hernot; Giuseppe Carlucci; Jan C. van de Voort; Francois Fay; Claudia Calcagno; Jun Tang; Amr Alaarg; Yiming Zhao; Seigo Ishino; et al. Nanobody-Facilitated Multiparametric PET/MRI Phenotyping of Atherosclerosis. JACC: Cardiovasc. Imaging 2019, 12, 2015-2026, .
  25. Hongda Li; Yanfang Wang; Jiwen Liu; Xiaoli Chen; Yunhao Duan; Xiaoyu Wang; Yajing Shen; Yashu Kuang; Tao Zhuang; Brain Tomlinson; et al. Endothelial Klf2-Foxp1-TGFβ signal mediates the inhibitory effects of simvastatin on maladaptive cardiac remodeling. Theranostics 2021, 11, 1609-1625, .
  26. Anna Pfenniger; Cindy Wong; Esther Sutter; Simon Cuhlmann; Sylvie Dunoyer-Geindre; François Mach; Anton J. Horrevoets; Paul C. Evans; Rob Krams; Brenda R. Kwak; et al. Shear stress modulates the expression of the atheroprotective protein Cx37 in endothelial cells. J. Mol. Cell. Cardiol. 2012, 53, 299-309, .
  27. Ziqiao Zhong; Lu Gan; Ziyi Feng; Wenhao Wang; Xin Pan; Chuanbin Wu; Ying Huang; Hydrogel local drug delivery systems for postsurgical management of tumors: Status Quo and perspectives. Mater. Today Bio 2024, 29, 101308, .
  28. Ziqiao Zhong; Lu Gan; Ziyi Feng; Wenhao Wang; Xin Pan; Chuanbin Wu; Ying Huang; Hydrogel local drug delivery systems for postsurgical management of tumors: Status Quo and perspectives. Mater. Today Bio 2024, 29, 101308, .
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