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    • We provide here direct evidences that AT receptors are

    2023-02-06

    We provide here direct evidences that AT1 receptors are active in ADSCs since Ang II induces intracellular Ca mobilization in these cells. Data obtained during the observation of Ca influxes led us to the search for the ADSCs subpopulation constantly expressing AT1 receptor. ADSCs are necessary for adipose tissue hyperplasia in obesity (Matsushita and Dzau, 2017): these ep4 antagonist can differentiate to adipocytes as well as promote vascularization of growing tissue by producing angiogenic growth factors. ADSCs treatment by Ang II before their transplantation to infarcted myocardium promotes the secretion of angiogenic growth factors by these cells and enhances their ability to stimulate blood vessel growth acting via AT1 receptor (Fan et al., 2015; Liu et al., 2015). Here we showed that exogenous and endogenous Ang II influence adipose differentiation of ADSCs. In line with previous observations (Brucher et al., 2007; Janke et al., 2006, 2002) our data indicate that Ang II inhibits adipose differentiation acting via AT1 receptor. For a first time here we report that ADSCs contain a subpopulation of cells constantly expressing AT1. These cells appeared to co-express AT2 receptor together with receptors for alternative angiotensin peptides. AT1const demonstrate the increased adipogenic differentiation in response to local RAS, which can be suppressed by AT2 inhibitor. Our in situ data demonstrate that in adipose tissue cells expressing AT2 receptor are predominately located at sites of increased cellularity between mature adipocytes. Such sites are often occupied by so-called angio-adipogenic clusters, responsible for expansion of adipose tissue during obesity (Kalinina et al., 2009). In contrast to previous reports, suggesting that AT1-dependent signaling dominates in adult cells co-expressing AT1 and AT2 receptors, our data indicate that ADSCs highly expressing angiotensin receptors respond predominately via type 2 receptor. These data allow us to suggest that this subpopulation of ADSCs retains embryonic RAS signaling, which correlates with our previous findings that ADSCs preserve embryonic adrenergic signaling regulation (Tyurin-Kuzmin et al., 2016). Possibly, AT1-dependent signaling could be suppressed by heteromerization with АТ2, as was previously demonstrated (AbdAlla et al., 2001; Yang et al., 2012).
    Conclusions The following are the supplementary data related to this article.
    Introduction The renin-angiotensin system (RAS) is an important regulatory system that maintains blood pressure, water and electrolyte balance, and cardiovascular homeostasis. Disorders in the RAS are involved in the development of cardiovascular disease [1]. Angiotensin II (Ang II), considered the core component of RAS, can promote vasoconstriction and aldosterone release, thereby regulating blood pressure and maintaining water and electrolyte balance [2]. These biological effects mainly depend upon the activation of angiotensin II type 1 receptor (AT1R) [3]. AT1R, which consists of 359 amino acids, is a typical G protein coupled receptor (GPCR) with a seven-fold transmembrane structure; there are two subtypes in rodents named AT1A and AT1B [4]. AT1R participates in a variety of signal transduction pathways, the conventional of which is the AT1R-PLC-PKC signaling pathway. After AT1R has been activated by its agonist, it activates phospholipase C (PLC) via the combination and activation of G proteins, and then hydrolyzes phosphatidylinositol 4,5-bisphosphate (PtdIns (4,5) P2) to generate inositol triphosphate (IP3) and Ca2+ signals [5]. In addition, activated AT1R can mediate the mitogen-activated protein kinase (MAPK) [6], and Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathways [7]. Distinct AT1R signaling pathways may be responsible for different cellular responses, such as proliferation, differentiation, and inflammation [8]. The activities of these signal transduction pathways are adjusted or terminated by the rearrangement of AT1R on the plasma membrane; the receptor on the membrane surface is not constant [9,10]. Depending on the various cell functions, AT1R can be quickly evacuated from the plasma membrane into the cytoplasm or transported from the cytoplasm to the plasma membrane. These plasma membrane–cytoplasm AT1R redistribution process, which is called internalization, can affect its membrane density and the intensity of the resulting signal [11,12], thereby avoiding the damage caused by continuous activation of AT1R. In this paper, recent advances in the mechanism of decreased AT1R internalization are summarized to deepen understanding of pathogenesis and provide a target for the treatment of cardiovascular diseases caused by receptor overactivation. The glossary of terms and abbreviations involved in this article are listed in Table 1.