Manipulating Intracellular Ca2+ Signals to Stimulate Therapeutic Angiogenesis in Cardiovascular Disorders

Moccia, Francesco; Berra‐Romani, Roberto; Rosti, Vittorio

doi:10.2174/1389201019666180808165309

Cited by 21 publications

(60 citation statements)

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“…This landmark discovery fostered an intense search for the most effective strategy to utilize EPCs for the regenerative therapy of ischemic disorders. However, the therapeutic use of EPCs has been hampered by inconsistent definitions and different protocols employed to isolate and expand them from peripheral and umbilical cord blood [ 15 , 16 , 17 ]. It has been demonstrated that two distinct and well-defined EPC subtypes may emerge from cultured mononuclear cells, which differ in their ontology and reparative mechanisms.…”

Section: Introductionmentioning

confidence: 99%

Therapeutic Potential of Endothelial Colony-Forming Cells in Ischemic Disease: Strategies to Improve their Regenerative Efficacy

Faris

Negri

Perna

et al. 2020

IJMS

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Cardiovascular disease (CVD) comprises a range of major clinical cardiac and circulatory diseases, which produce immense health and economic burdens worldwide. Currently, vascular regenerative surgery represents the most employed therapeutic option to treat ischemic disorders, even though not all the patients are amenable to surgical revascularization. Therefore, more efficient therapeutic approaches are urgently required to promote neovascularization. Therapeutic angiogenesis represents an emerging strategy that aims at reconstructing the damaged vascular network by stimulating local angiogenesis and/or promoting de novo blood vessel formation according to a process known as vasculogenesis. In turn, circulating endothelial colony-forming cells (ECFCs) represent truly endothelial precursors, which display high clonogenic potential and have the documented ability to originate de novo blood vessels in vivo. Therefore, ECFCs are regarded as the most promising cellular candidate to promote therapeutic angiogenesis in patients suffering from CVD. The current briefly summarizes the available information about the origin and characterization of ECFCs and then widely illustrates the preclinical studies that assessed their regenerative efficacy in a variety of ischemic disorders, including acute myocardial infarction, peripheral artery disease, ischemic brain disease, and retinopathy. Then, we describe the most common pharmacological, genetic, and epigenetic strategies employed to enhance the vasoreparative potential of autologous ECFCs by manipulating crucial pro-angiogenic signaling pathways, e.g., extracellular-signal regulated kinase/Akt, phosphoinositide 3-kinase, and Ca2+ signaling. We conclude by discussing the possibility of targeting circulating ECFCs to rescue their dysfunctional phenotype and promote neovascularization in the presence of CVD.

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Section: Introductionmentioning

confidence: 99%

Therapeutic Potential of Endothelial Colony-Forming Cells in Ischemic Disease: Strategies to Improve their Regenerative Efficacy

Faris

Negri

Perna

et al. 2020

IJMS

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“…Nevertheless, TRPV4-mediated extracellular Ca 2+ entry supported AA-evoked intracellular Ca 2+ signals, NO release and PB-ECFC proliferation (Dragoni et al, 2015a). This feature could become therapeutically relevant as AA is massively released in circulation during myocardial ischemia and upon brain damage (Moccia et al, 2018a). Unlike TRPV4, TRPV1 activation is per se sufficient to induce ECFC proliferation.…”

Section: The Role Of Trpv1 and Trpv4 In Vasculogenesismentioning

confidence: 98%

“…Genetic (with specific siRNAs) and pharmacological (with Pyr3) manipulation revealed that TRPC3-mediated extracellular Ca 2+ entry triggers the dynamic interplay between InsP 3 Rs and SOCE which shapes the spiking Ca 2+ response to VEGF, thereby promoting UCB-ECFC proliferation (Dragoni et al, 2013). It has been suggested that TRPC3 involvement is responsible for the higher frequency of VEGF-induced intracellular Ca 2+ oscillations in UCB-ECFCs, which is associated to their higher proliferative potential (Moccia et al, 2018a). This observation led to the hypothesis that the exogenous insertion of TRPC3 might rejuvenate the reparative phenotype of senescent/aging UCB-ECFCs, thereby improving the efficacy of autologous cell-based therapy in ischemic patients (Moccia et al, 2018a).…”

Section: The Role Of Trpc1 and Trpc3 In Vasculogenesismentioning

confidence: 99%

“…It has been suggested that TRPC3 involvement is responsible for the higher frequency of VEGF-induced intracellular Ca 2+ oscillations in UCB-ECFCs, which is associated to their higher proliferative potential (Moccia et al, 2018a). This observation led to the hypothesis that the exogenous insertion of TRPC3 might rejuvenate the reparative phenotype of senescent/aging UCB-ECFCs, thereby improving the efficacy of autologous cell-based therapy in ischemic patients (Moccia et al, 2018a).…”

Section: The Role Of Trpc1 and Trpc3 In Vasculogenesismentioning

confidence: 99%

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Endothelial Transient Receptor Potential Channels and Vascular Remodeling: Extracellular Ca2 + Entry for Angiogenesis, Arteriogenesis and Vasculogenesis

et al. 2020

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Vasculogenesis, angiogenesis and arteriogenesis represent three crucial mechanisms involved in the formation and maintenance of the vascular network in embryonal and post-natal life. It has long been known that endothelial Ca 2+ signals are key players in vascular remodeling; indeed, multiple pro-angiogenic factors, including vascular endothelial growth factor, regulate endothelial cell fate through an increase in intracellular Ca 2+ concentration. Transient Receptor Potential (TRP) channel consist in a superfamily of non-selective cation channels that are widely expressed within vascular endothelial cells. In addition, TRP channels are present in the two main endothelial progenitor cell (EPC) populations, i.e., myeloid angiogenic cells (MACs) and endothelial colony forming cells (ECFCs). TRP channels are polymodal channels that can assemble in homo-and heteromeric complexes and may be sensitive to both pro-angiogenic cues and subtle changes in local microenvironment. These features render TRP channels the most versatile Ca 2+ entry pathway in vascular endothelial cells and in EPCs. Herein, we describe how endothelial TRP channels stimulate vascular remodeling by promoting angiogenesis, arteriogenesis and vasculogenesis through the integration of multiple environmental, e.g., extracellular growth factors and chemokines, and intracellular, e.g., reactive oxygen species, a decrease in Mg 2+ levels, or hypercholesterolemia, stimuli. In addition, we illustrate how endothelial TRP channels induce neovascularization in response to synthetic agonists and small molecule drugs. We focus the attention on TRPC1, TRPC3, TRPC4, TRPC5, TRPC6, TRPV1, TRPV4, TRPM2, TRPM4, TRPM7, TRPA1, that were shown to be involved in angiogenesis, arteriogenesis and vasculogenesis. Finally, we discuss the role of endothelial TRP channels in aberrant tumor vascularization by focusing on TRPC1, TRPC3, TRPV2, TRPV4, TRPM8, and TRPA1. These observations suggest that endothelial TRP channels represent potential therapeutic targets in multiple disorders featured by abnormal vascularization, including cancer, ischemic disorders, retinal degeneration and neurodegeneration.

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“…The depletion of Ca 2+ from the endoplasmic reticulum leads to the accumulation of stromal interaction molecule 1 protein in the endoplasmic reticulum membrane, which eventually evokes Ca 2+ in ux by activating Orai channels located in the cell membrane [13]. SOCE participates in various physiological and pathological activities, such as cell proliferation and migration regulation, immune response, and cancer development [14][15][16]. However, the regulatory effect of SOCE in human lens epithelial cells has been rarely investigated.…”

Section: Introductionmentioning

confidence: 99%

Oxidized low-density lipoprotein enhances Orai3 expression levels to increase proliferation of human lens epithelial cells

Zhang¹,

Bai²,

Fang³

et al. 2020

Preprint

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Background Serum lipid levels, especially of oxidized low-density lipoprotein (oxLDL), are related to the development of cataracts, but the mechanisms underlying the role of oxLDL in cataract development in human lens epithelial cells (HLEpiCs) remain unclear. Calcium (Ca2+) overload is also known to be involved in lens turbidity. Store-operated Ca2+ entry (SOCE) is an important pathway mediating Ca2+ influx in lens epithelial cells. The Orai family proteins, which form a type of SOCE channel, localize at the plasma membrane and control Ca2+ influx in response to the depletion of Ca2+ stores in the endoplasmic reticulum. Methods In the present study, we used RNA sequencing, western blot analyses, cell proliferation assays, Ca2+ measurements, and small interfering (si)RNA transfections to investigate the effects of oxLDL on SOCE and proliferation of human lens epithelial cells (HLEpiCs). Results The key findings of our study that suggest this conclusion are that (1) oxLDL enhances the expression levels of Orai3, but not Orai1 or Orai2, in HLEpiCs in vitro; (2) oxLDL significantly increases the proliferation of HLEpiCs in a concentration-dependent manner; (3) oxLDL significantly increases ATP-induced SOCE without affecting Ca2+ release in HLEpiCs; and (4) knockdown of Orai3 significantly reduces cell proliferation and ATP-induced SOCE in HLEpiCs. Conclusions These findings suggest that Ca2+ signaling altered by overexpression of Orai3 may be a mechanism whereby oxLDL increases HLEpiC proliferation to contribute to the development of cataract. Thus, Orai3 may be a target warranting development for the treatment of cataract associated with obesity or hyperlipidemia.

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Manipulating Intracellular Ca2+ Signals to Stimulate Therapeutic Angiogenesis in Cardiovascular Disorders

Cited by 21 publications

References 0 publications

Therapeutic Potential of Endothelial Colony-Forming Cells in Ischemic Disease: Strategies to Improve their Regenerative Efficacy

Therapeutic Potential of Endothelial Colony-Forming Cells in Ischemic Disease: Strategies to Improve their Regenerative Efficacy

Endothelial Transient Receptor Potential Channels and Vascular Remodeling: Extracellular Ca2 + Entry for Angiogenesis, Arteriogenesis and Vasculogenesis

Oxidized low-density lipoprotein enhances Orai3 expression levels to increase proliferation of human lens epithelial cells

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