Group 1 metabotropic glutamate receptors trigger glutamate-induced intracellular Ca2+ signals and nitric oxide release in human brain microvascular endothelial cells

Negri, Sharon; Faris, Pawan; Pellavio, Giorgia; Botta, Laura; Orgiu, Matteo; Forcaia, Greta; Sancini, Giulio; Laforenza, Umberto; Moccia, Francesco

doi:10.1007/s00018-019-03284-1

Cited by 38 publications

(64 citation statements)

References 105 publications

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“…Finally, ex vivo ECFC expansion could be achieved by stimulating an increase in intracellular Ca 2+ concentration ([Ca 2+ ] i ), which has long been known to stimulate ECFC proliferation [ 159 , 160 , 161 , 162 ]. For instance, the liposomal delivery of nicotinic acid adenine dinucleotide phosphate (NAADP), the physiological agonist of endolysosomal two-pore channels (TPCs) [ 163 , 164 , 165 , 166 ], stimulated ECFC proliferation in a Ca 2+ -dependent manner [ 15 ]. Likewise, the lipid messenger arachidonic acid promoted ex vivo ECFC expansion by inducing extracellular Ca 2+ entry through Transient Receptor Potential Vanilloid 4 (TRPV4) channel and then recruiting the endothelial NO synthase (eNOS) [ 167 , 168 ].…”

Section: Manipulation Of Pro-angiogenic Signaling Pathways To Imprmentioning

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: Manipulation Of Pro-angiogenic Signaling Pathways To Imprmentioning

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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“…Electrophysiological recordings from Trpc3 KO Purkinje cell have established that TRPC3 channels mediate slow postsynaptic currents (sEPSCs) in response to stimulation of subtype I metabotropic glutamate receptors (mGluR1) [123,129]. When stimulated, mGluR1 activates PLCβ to hydrolize PIP 2 into IP 3 and DAG [131]. As a consequence of IP 3 -induced endoplasmic reticulum (ER)-Ca 2+ store depletion, the ER-Ca 2+ sensor Stromal Interaction Molecule 1 (STIM1) translocates to peripheral ER cisternae, where it aggregates within sub-membranal clusters and gates Orai1 [132] and/or TRPC3 channels [133][134][135][136].…”

Section: Mutations In the Trpc3 Genementioning

confidence: 99%

Disrupted Calcium Signaling in Animal Models of Human Spinocerebellar Ataxia (SCA)

Prestori

Moccia

D’Angelo

2019

IJMS

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Spinocerebellar ataxias (SCAs) constitute a heterogeneous group of more than 40 autosomal-dominant genetic and neurodegenerative diseases characterized by loss of balance and motor coordination due to dysfunction of the cerebellum and its efferent connections. Despite a well-described clinical and pathological phenotype, the molecular and cellular events that underlie neurodegeneration are still poorly undaerstood. Emerging research suggests that mutations in SCA genes cause disruptions in multiple cellular pathways but the characteristic SCA pathogenesis does not begin until calcium signaling pathways are disrupted in cerebellar Purkinje cells. Ca2+ signaling in Purkinje cells is important for normal cellular function as these neurons express a variety of Ca2+ channels, Ca2+-dependent kinases and phosphatases, and Ca2+-binding proteins to tightly maintain Ca2+ homeostasis and regulate physiological Ca2+-dependent processes. Abnormal Ca2+ levels can activate toxic cascades leading to characteristic death of Purkinje cells, cerebellar atrophy, and ataxia that occur in many SCAs. The output of the cerebellar cortex is conveyed to the deep cerebellar nuclei (DCN) by Purkinje cells via inhibitory signals; thus, Purkinje cell dysfunction or degeneration would partially or completely impair the cerebellar output in SCAs. In the absence of the inhibitory signal emanating from Purkinje cells, DCN will become more excitable, thereby affecting the motor areas receiving DCN input and resulting in uncoordinated movements. An outstanding advantage in studying the pathogenesis of SCAs is represented by the availability of a large number of animal models which mimic the phenotype observed in humans. By mainly focusing on mouse models displaying mutations or deletions in genes which encode for Ca2+ signaling-related proteins, in this review we will discuss the several pathogenic mechanisms related to deranged Ca2+ homeostasis that leads to significant Purkinje cell degeneration and dysfunction.

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“…In research kainate is used to induce epilepsy in animal experiments in which not only excitotoxicity and neuronal damage but also blood-brain barrier (BBB) leakage and neurovascular changes are observed [5]. Among the excitatory compounds the effect of glutamate and the presence of glutamate receptors on brain endothelial cells have been described previously by our group and others [6][7][8][9][10][11], but kainate effects and receptors are less investigated at the level of BBB.…”

Section: Introductionmentioning

confidence: 99%

Simvastatin, edaravone and dexamethasone protect against kainate-induced brain endothelial cell damage

Barna

Walter

Harazin

et al. 2020

Fluids Barriers CNS

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Background: Excitotoxicity is a central pathological pathway in many neurological diseases with blood-brain barrier (BBB) dysfunction. Kainate, an exogenous excitotoxin, induces epilepsy and BBB damage in animal models, but the direct effect of kainate on brain endothelial cells has not been studied in detail. Our aim was to examine the direct effects of kainate on cultured cells of the BBB and to test three anti-inflammatory and antioxidant drugs used in clinical practice, simvastatin, edaravone and dexamethasone, to protect against kainate-induced changes.Methods: Primary rat brain endothelial cell, pericyte and astroglia cultures were used to study cell viability by impedance measurement. BBB permeability was measured on a model made from the co-culture of the three cell types. The production of nitrogen monoxide and reactive oxygen species was followed by fluorescent probes. The mRNA expression of kainate receptors and nitric oxide synthases were studied by PCR.Results: Kainate damaged brain endothelial cells and made the immunostaining of junctional proteins claudin-5 and zonula occludens-1 discontinuous at the cell border indicating the opening of the barrier. The permeability of the BBB model for marker molecules fluorescein and albumin and the production of nitric oxide in brain endothelial cells were increased by kainate. Simvastatin, edaravone and dexamethasone protected against the reduced cell viability, increased permeability and the morphological changes in cellular junctions caused by kainate. Dexamethasone attenuated the elevated nitric oxide production and decreased the inducible nitric oxide synthase (NOS2/iNOS) mRNA expression increased by kainate treatment. Conclusion:Kainate directly damaged cultured brain endothelial cells. Simvastatin, edaravone and dexamethasone protected the BBB model against kainate-induced changes. Our results confirmed the potential clinical usefulness of these drugs to attenuate BBB damage. Publisher's NoteSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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Group 1 metabotropic glutamate receptors trigger glutamate-induced intracellular Ca2+ signals and nitric oxide release in human brain microvascular endothelial cells

Cited by 38 publications

References 105 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

Disrupted Calcium Signaling in Animal Models of Human Spinocerebellar Ataxia (SCA)

Simvastatin, edaravone and dexamethasone protect against kainate-induced brain endothelial cell damage

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