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Short Communication - (2025)Volume 16, Issue 1
Fibrosis is often an end-stage manifestation of chronic inflammatory diseases, affecting any tissue or organ in the body due to uncontrolled deposition of extracellular matrix molecules. Vascular fibrosis, characterized by the accumulation of extracellular matrix components, leads to vessel stiffness and is associated with various cardiovascular diseases. Ion channels in the cardiovascular system are important for maintaining normal physiological functions and play significant roles in processes such as ion transport and cell differentiation. Ion channels on fibroblasts, smooth muscle cells, and endothelial cells may be involved in vascular fibrotic remodeling. Understanding the mechanisms of vascular fibrosis and reversing this pathology could enhance our knowledge and treatment of fibrosis. This letter discusses ion channels known to contribute to vascular fibrotic remodeling and potential therapeutic targets for treating vascular fibrosis and promoting post-injury vascular repair
Ion channels, Vascular wall, Fibrosis, Vascular remodeling
Vascular fibrosis is often caused by the excessive deposition of extracellular matrix components such as collagen and fibronectin, leading to reduced vascular compliance, luminal constriction and wall thickening, which can result in various cardiovascular diseases like aneurysms and atherosclerosis [1,2]. Ion channels on the vascular wall are involved in the pathogenesis of vascular fibrosis and may serve as potential therapeutic targets [3]. Early intervention could potentially halt or delay this pathology, making the elucidation of vascular fibrosis mechanisms beneficial for research on reversing vascular remodeling. Next, this letter briefly introduces the ion channels associated with vascular fibrosis remodeling.
Transient Receptor Potential (TRP) channels and vascular fibrotic remodeling
The TRP superfamily in humans comprises 28 types and 6 subgroups [4]. TRP channels play a significant role in calcium ion entry into cells [5]. Studies indicate that many TRP channels are pivotal in fibrotic diseases across various organs [4].
This section will introduce three TRP channels related to fibrosis:
TRPM7: Transient Receptor Potential Melastatin 7 (TRPM7) is widely expressed in the human body and is permeable to divalent cations such as Zn2+, Ca2+ and Mg2+ [6-8]. Many divalent cations, like magnesium, play a vital role in regulating physiological activities and their depletion can lead to endothelial dysfunction, arterial remodeling and hypertension [7]. Since TRPM7 channels allow the passage of these divalent cations, damage to this channel can alter the levels of these ions in the body, potentially leading to inflammation or fibrosis [9]. Targeting this channel for treatment may, provide vascular protection, although the efficacy may vary across different animal models.
TRPC6: Transient Receptor Potential Cation Channel 6 (TRPC6) is a nonselective channel permeable to Na+ and Ca2+, regulated by second messengers and phosphorylation. It plays a key role in Store-Operated Calcium Entry (SOCE), which is vital for cellular calcium homeostasis [10]. In pulmonary hypertension, TRPC6 upregulation in Pulmonary Artery Smooth Muscle Cells (PASMCs) increases SOCE, contributing to pulmonary vascular remodeling and fibrosis [11]. TRPC6 is also involved in fibroblast transformation and Endothelial Mesenchymal Transformation (EndMT) processes, suggesting it could be a therapeutic target to inhibit vascular remodeling and fibrosis in pulmonary hypertension [12].
TRPV4: Transient Receptor Potential Vanilloid 4 (TRPV4) channels is associated with skin fibrosis in scleroderma and increased TRPV4 channel activity is observed in lung fibroblasts of patients with idiopathic pulmonary fibrosis [13,14]. Knockout of TRPV4 in mice reduces fibrosis in organs such as the lungs and heart [15]. In summary, TRPV4 plays an important role in fibroblast activation and extracellular matrix remodeling, and its inhibition alleviates fibrosis in organs like the heart and lungs.
Calcium activation of potassium channels (KCa) and vascular fibrosis remodeling
The KCa family plays an essential role in cellular excitability and is categorized into three types based on their conductance: Small conductance (SK, ~4-14 pS), medium conductance (IK, ~32-39 pS) and large conductance (BK, ~200-300 pS) channels [16]. In pathological conditions, calcium-activated potassium channels are widely involved in the remodeling process of vascular fibrosis. BK, IK and SK calcium-activated potassium channels on vascular wall cells promote vascular inflammation by activating PI3K/Akt pathway. Activation of the classic fibrotic pathways such as Smad2/3, P38 and Ras ultimately leads to vascular remodeling and adverse progression of fibrosis.
Other ion channels on vascular cells and vascular fibrosis remodeling
In addition to TRP and KCa ion channels widely involved in vascular fibrosis, other types of ion channels include Piezo1, the mechanically sensitive ion channel on smooth muscle cells, the L-type calcium ion channel, the ORAI1/STIM1 channel, and the Volume-Regulated Anion Channel (VRAC) on fibroblasts. The current activity and downstream signals of these channels are involved in the regulation of vascular cell proliferation, migration and differentiation. Pathologically, they also activate TGF-β/Smad and p38-MAPK signaling pathways, which play a key role in the occurrence and progression of fibrosis.
Vascular fibrosis is present in many fibrotic diseases and contributes to disease progression and deterioration. It primarily results from the deposition and reorganization of excessive extracellular matrix components, a process mediated by vascular smooth muscle cells, endothelial cells, and fibroblasts. Numerous ion channels on these cells are involved in vascular fibrosis. Understanding the mechanisms and downstream signaling pathways of these ion channels in vascular fibrosis could provide strategies and insights for future anti-fibrotic therapies.
This research was supported by National Natural Science Foundation of China (32171099, and 82070502), Department of Science and Technology of Sichuan Province (2024NSFSC0709, 2023NSFSC0576) and Luzhou-Southwest Medical University Joint Project (2024LZXNYDJ014).
There is no conflict of interest
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Citation: Liao X, Zhang X, Tian H, Cheng J (2025). Frontier Progress on the Role and Mechanism of Ion Channels on Vascular Wall Cells in Vascular Fibrosis Remodeling. J Cell Sci Therapy. 16:492.
Received: 02-Dec-2024, Manuscript No. JCEST-24-35534; Editor assigned: 04-Dec-2024, Pre QC No. JCEST-24-35534 (PQ); Reviewed: 18-Dec-2024, QC No. JCEST-24-35534; Revised: 26-Dec-2024, Manuscript No. JCEST-24-35534 (R); Published: 03-Jan-2025 , DOI: 10.35248/2157-7013.25.16.492
Copyright: © 2025 Liao X, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Sources of funding : This research was supported by National Natural Science Foundation of China (32171099, and 82070502), Department of Science and Technology of Sichuan Province (2024NSFSC0709, 2023NSFSC0576) and Luzhou-Southwest Medical University Joint Project (2024LZXNYDJ014).