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Activation of ?-adrenergic receptors is required for elevated ?1A-adrenoreceptors expression and signaling in mesenchymal stromal cells.

ABSTRACT: Sympathetic neurons are important components of mesenchymal stem cells (MSCs) niche and noradrenaline regulates biological activities of these cells. Here we examined the mechanisms of regulation of MSCs responsiveness to noradrenaline. Using flow cytometry, we demonstrated that ?1A adrenergic receptors isoform was the most abundant in adipose tissue-derived MSCs. Using calcium imaging in single cells, we demonstrated that only 6.9?±?0.8% of MSCs responded to noradrenaline by intracellular calcium release. Noradrenaline increases MSCs sensitivity to catecholamines in a transitory mode. Within 6?hrs after incubation with noradrenaline the proportion of cells responding by Ca(2+) release to the fresh noradrenaline addition has doubled but declined to the baseline after 24?hrs. Increased sensitivity was due to the elevated quantities of ?1A-adrenergic receptors on MSCs. Such elevation depended on the stimulation of ?-adrenergic receptors and adenylate cyclase activation. The data for the first time clarify mechanisms of regulation of MSCs sensitivity to noradrenaline.

SUBMITTER: Tyurin-Kuzmin PA

PROVIDER: S-EPMC5011778 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

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Activation of β-adrenergic receptors is required for elevated α1A-adrenoreceptors expression and signaling in mesenchymal stromal cells.

Tyurin-Kuzmin Pyotr A PA Fadeeva Julia I JI Kanareikina Margarita A MA Kalinina Natalia I NI Sysoeva Veronika Yu VY Dyikanov Daniyar T DT Stambolsky Dmitriy V DV Tkachuk Vsevolod A VA

Scientific reports 20160906

Sympathetic neurons are important components of mesenchymal stem cells (MSCs) niche and noradrenaline regulates biological activities of these cells. Here we examined the mechanisms of regulation of MSCs responsiveness to noradrenaline. Using flow cytometry, we demonstrated that α1A adrenergic receptors isoform was the most abundant in adipose tissue-derived MSCs. Using calcium imaging in single cells, we demonstrated that only 6.9 ± 0.8% of MSCs responded to noradrenaline by intracellular calci ...[more]

PMID: 27596381

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Project description:Stimulation of cardiac ?1A-adrenergic receptors (?1A-AR) has been proposed for treatment of heart failure, since it increases myocardial contractility. We investigated a different mechanism, induction of angiogenesis.Four to 6 weeks after permanent coronary artery occlusion, transgenic rats with cardiomyocyte-specific ?1A-adrenergic receptor overexpression had less remodeling than their nontransgenic littermates, with less fibrosis, hypertrophy and lung weight, and preserved left ventricular ejection fraction and wall stress (all P<0.05). Coronary blood flow, measured with microspheres, increased in the infarct zone in transgenic rats compared with nontransgenic littermates (1.4±0.2 versus 0.5±0.08 mL min(-1) g(-1); P<0.05), which is consistent with angiogenesis, as reflected by a 20% increase in capillary density in the zone adjacent to the infarct. The question arose, how does transgenic overexpression of a gene in cardiomyocytes induce angiogenesis? We identified a paracrine mechanism, whereby vascular endothelial growth factor-A mRNA and protein were increased in isolated transgenic cardiomyocytes and also by nontransgenic littermate cardiomyocytes treated with an ?1A-agonist, resulting in angiogenesis. Conditioned medium from cultured cardiomyocytes treated with an ?1A agonist enhanced human umbilical vein endothelial cell tubule formation, which was blocked by an anti-vascular endothelial growth factor-A antibody. Moreover, improved cardiac function, blood flow, and increased capillary density after chronic coronary artery occlusion in transgenic rats were blocked by either a mitogen ERK kinase (MEK) or a vascular endothelial growth factor-A inhibitor.Cardiomyocyte-specific overexpression of the ?1A-adrenergic receptors resulted in enhanced MEK-dependent cardiomyocyte vascular endothelial growth factor-A expression, which stimulates angiogenesis via a paracrine mechanism involving heterocellular cardiomyocyte/endothelial cell signaling, protecting against remodeling and heart failure after chronic coronary artery occlusion.

Project description:In Alzheimer's disease (AD) pathophysiology, plaque and tangle accumulation trigger an inflammatory response that mounts positive feed-back loops between inflammation and protein aggregation, aggravating neurite damage and neuronal death. One of the earliest brain regions to undergo neurodegeneration is the locus coeruleus (LC), the predominant site of norepinephrine (NE) production in the central nervous system (CNS). In animal models of AD, dampening the impact of noradrenergic signaling pathways, either through administration of beta blockers or pharmacological ablation of the LC, heightened neuroinflammation through increased levels of pro-inflammatory mediators. Since microglia are the resident immune cells of the CNS, it is reasonable to postulate that they are responsible for translating the loss of NE tone into exacerbated disease pathology. Recent findings from our lab demonstrated that noradrenergic signaling inhibits microglia dynamics via β2 adrenergic receptors (β2ARs), suggesting a potential anti-inflammatory role for microglial β2AR signaling. Thus, we hypothesize that microglial β2 adrenergic signaling is progressively impaired during AD progression, which leads to the chronic immune vigilant state of microglia that worsens disease pathology. First, we characterized changes in microglial β2AR signaling as a function of amyloid pathology. We found that LC neurons and their projections degenerate early and progressively in the 5xFAD mouse model of AD; accompanied by mild decrease in the levels of norepinephrine and its metabolite normetanephrine. Interestingly, while 5xFAD microglia, especially plaque-associated microglia, significant downregulated β2AR gene expression early in amyloid pathology, they did not lose their responsiveness to β2AR stimulation. Most importantly, we demonstrated that specific microglial β2AR deletion worsened disease pathology while chronic β2AR stimulation resulted in attenuation of amyloid pathology and associated neuritic damage, suggesting microglial β2AR might be used as potential therapeutic target to modify AD pathology.

Project description:AimsTo determine the mechanisms by which the ?1A-adrenergic receptor (AR) regulates cardiac contractility.BackgroundWe reported previously that transgenic mice with cardiac-restricted ?1A-AR overexpression (?1A-TG) exhibit enhanced contractility but not hypertrophy, despite evidence implicating this G?q/11-coupled receptor in hypertrophy.MethodsContractility, calcium (Ca(2+)) kinetics and sensitivity, and contractile proteins were examined in cardiomyocytes, isolated hearts and skinned fibers from ?1A-TG mice (170-fold overexpression) and their non-TG littermates (NTL) before and after ?1A-AR agonist stimulation and blockade, angiotensin II (AngII), and Rho kinase (ROCK) inhibition.ResultsHypercontractility without hypertrophy with ?1A-AR overexpression is shown to result from increased intracellular Ca(2+) release in response to agonist, augmenting the systolic amplitude of the intracellular Ca(2+) concentration [Ca(2+)]i transient without changing resting [Ca(2+)]i. In the absence of agonist, however, ?1A-AR overexpression reduced contractility despite unchanged [Ca(2+)]i. This hypocontractility is not due to heterologous desensitization: the contractile response to AngII, acting via its G?q/11-coupled receptor, was unaltered. Rather, the hypocontractility is a pleiotropic signaling effect of the ?1A-AR in the absence of agonist, inhibiting RhoA/ROCK activity, resulting in hypophosphorylation of both myosin phosphatase targeting subunit 1 (MYPT1) and cardiac myosin light chain 2 (cMLC2), reducing the Ca(2+) sensitivity of the contractile machinery: all these effects were rapidly reversed by selective ?1A-AR blockade. Critically, ROCK inhibition in normal hearts of NTLs without ?1A-AR overexpression caused hypophosphorylation of both MYPT1 and cMLC2, and rapidly reduced basal contractility.ConclusionsWe report for the first time pleiotropic ?1A-AR signaling and the physiological role of RhoA/ROCK signaling in maintaining contractility in the normal heart.

Dataset Information

Activation of ?-adrenergic receptors is required for elevated ?1A-adrenoreceptors expression and signaling in mesenchymal stromal cells.

Publications

Activation of β-adrenergic receptors is required for elevated α1A-adrenoreceptors expression and signaling in mesenchymal stromal cells.

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