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  • According to Laplace s law loss of myogenic

    2022-01-20

    According to Laplace’s law, loss of myogenic response would increase wall stress and tension in downstream vessels and subsequently induce endothelial dysfunction and arterial stiffness [36]. Indeed, we found that arteries from FPR-1 KO mice presented with a leftward shift in the stress-strain curve and decreased distensibility, suggesting that these arteries are stiffer in basal conditions. One important concept of vascular mechanics is that proportional composition of blood vessels influences passive distensibility of the vessel wall. The concept considers the relation between structure and mechanics of the vessel wall in terms of the elastic moduli of individual wall components [37]. In an interesting study, Baumbach et al. Baumbach et al. [37] showed that in hypertension one mechanism that may protect cerebral vessels is increases in passive distensibility of cerebral arterioles. They suggested that increases in passive distensibility of cerebral arterioles, therefore, may increase effectiveness of autoregulation of cerebral blood flow in SHRSP. Likewise, in the present manuscript, we observed that arteries from FPR-1 KO animals presented decreased in distensibility and myogenic tone when compared to WT. This suggests that impairments in distensibility would lead to damage of myogenic tone and, subsequently a stiffer artery. As described above, we also found that arteries of FPR-1 KO exhibit reduction in the internal and external diameter and, consequently, a reduction in cross-sectional area (CSA) which suggests an inward hypotrophic remodeling. It is known that circumferencial wall stress and wall shear stress are important driving forces during development of the arterial wall and in the adult [38,39]. Vascular remodeling can result in either an increase, no change, or a decrease in the amount of material, that there should be a sub-classification into hypertrophic, eutrophic, and hypotrophic remodeling, respectively [40]. Only few studies were able to observe inward hypotrophic remodeling [39]. Accordingly, it is known that reduced blood flow results in inward hypotrophic remodeling accompanied by hyporeactivity of the arterial smooth muscle [39]. In the present manuscript, we also observed hyporeactivity to adrenergic receptor agonist, however a causative relationship between inward hypotrophic remodeling, blood flow and hyporeactivity was not assessed in the present study, and will be the subject of future studies. Overall, our results reveal a unique function for FPR-1 in mediating vascular plasticity during physiological conditions. Upon activation (by agonist or stretch), FPR-1 triggers NBI 27914 hydrochloride polymerization by mechanisms that are still unclear (Fig. 9). However, based on preliminary data we could infer that FPR-1 may act via an integrated network with Cav 1.2, RhoA, and actin polymerization. Future studies are needed to dissect the mechanisms associated with FPR-1 activation and its functions as a mechanosensor-like receptor and vascular-immuno network during perturbations.
    Conflict of interest
    Author contributions All authors approved the final version of the manuscript. C.F.W. conceived the experiment design, analyzed the data and wrote the manuscript. C.G.M., support the interpretation of the data and performed the experiments; F.B.C., T.S. and M.M. performed the experiments. R.C.W. revised it critically for important intellectual content.
    Acknowledgements
    Formyl-Peptide Receptors and Their Ligands in Health and Disease The innate immune system discriminates between self and foreign cells or substances through pattern recognition receptors (PRRs; see Glossary), which recognize pathogen-associated molecular patterns (PAMPs). The Toll-like receptors (TLRs) are the best studied PRRs, whereas formyl-peptide receptors (FPRs), also considered PRRs, have not been studied in nearly as much depth. FPRs belong to the family of seven-transmembrane G protein-coupled receptors (GPCRs), many of which are involved in host defense against bacterial infections and clearance of damaged cells [1]. FPRs are well conserved among mammals [1]. The human FPRs (FPR1, FPR2, and FPR3) are primarily regarded as myeloid cell receptors, as they are mainly expressed in neutrophils (except FPR3) and monocytes [2]. In addition to myeloid cells, FPR1 is also expressed in astrocytes, microglia, hepatocytes, and immature dendritic cells, whereas FPR2 is expressed in astrocytoma cells, epithelial cells, hepatocytes, microvascular endothelial cells, and neuroblastoma cells [2]. FPR1 generally recognizes short peptides of approximately 3–5 amino acids that start with N-formylmethionine [3]; these peptides are cleavage products of bacterial and mitochondrial proteins. One of the most potent ligands for human FPR1 is the Escherichia coli-derived peptide N-formylmethionyl-leucyl-phenylalanine (fMLF) [1]. By contrast, FPR2 is a low-affinity receptor for many of the potent FPR1 agonists and is activated by longer peptides with α-helical, amphipathic properties [4]. The most prominent bacterial FPR2 ligands are the staphylococcal-derived phenol-soluble modulins (PSMs)[5]. In addition to staphylococci, many other bacteria and viruses produce FPR2 ligands, including Listeria monocytogenes[6], Enterococcus faecium[7], Helicobacter pylori[8], Streptococcus pneumoniae9, 10, and human immunodeficiency virus (HIV) 11, 12, 13, 14, 15 (Table 1). In addition, many host-derived peptide and lipid FPR agonists (Table 1) have been shown to be associated with inflammation and have demonstrated a preference for human and mouse FPR2 [2]. For example, administration of resolvin D1 (RvD1) and (; both FPR2 ligands) has been shown to resolve inflammation in a murine model of Alzheimer’s disease [16]. FPR3 ligands hardly overlap with those of FPR1 or FPR2, and the overall function of the FPR3 receptor remains unclear (Box 1). Activation of FPRs in myeloid cells results in dissociation of heterotrimeric G proteins coupled to FPRs into α and βγ subunits [17]. Multiple signaling pathways activated by the dissociated G proteins are involved in a variety of antimicrobial cellular responses, such as the migration of these cells to peritoneal infection sites, phagocytosis, the release of reactive oxygen species and antimicrobial peptides (AMPs), such as LL-37, as well as the expression of chemokines, such as interleukin (IL)-8 (Figure 1). These have been shown using in vivo mouse models, as well as primary mouse and human leukocytes 5, 6, 18, 19.