Endothelial cells are, by number, one of the most abundant cell types in the heart and active players in cardiac physiology and pathology. Coronary angiogenesis plays a vital role in maintaining cardiac vascularization and perfusion during physiological and pathological hypertrophy. On the other hand, a reduction in cardiac capillary density with subsequent tissue hypoxia, cell death and interstitial fibrosis contributes to the development of contractile dysfunction and heart failure, as suggested by clinical as well as experimental evidence. Although the molecular causes underlying the inadequate (with respect to the increased oxygen and energy demands of the hypertrophied cardiomyocyte) cardiac vascularization developing during pathological hypertrophy are incompletely understood. Research efforts over the past years have discovered interesting mediators and potential candidates involved in this process. In this review article, we will focus on the vascular changes occurring during cardiac hypertrophy and the transition toward heart failure both in human disease and preclinical models. We will summarize recent findings in transgenic mice and experimental models of cardiac hypertrophy on factors expressed and released from cardiomyocytes, pericytes and inflammatory cells involved in the paracrine (dys)regulation of cardiac angiogenesis. Moreover, we will discuss major signaling events of critical angiogenic ligands in endothelial cells and their possible disturbance by hypoxia or oxidative stress. In this regard, we will particularly highlight findings on negative regulators of angiogenesis, including protein tyrosine phosphatase-1B and tumor suppressor p53, and how they link signaling involved in cell growth and metabolic control to cardiac angiogenesis. Besides endothelial cell death, phenotypic conversion and acquisition of myofibroblast-like characteristics may also contribute to the development of cardiac fibrosis, the structural correlate of cardiac dysfunction. Factors secreted by  endothelial cells and their effects on cardiomyocytes including hypertrophy, contractility and fibrosis, close the vicious circle of reciprocal cell-cell interactions within the heart during pathological hypertrophy remodeling. Vice versa, activated or dysfuntional endothelial cells may also affect the function of other cell types in the heart, including myocytes and non-myocytes. However, these mechanisms fail to stimulate capillary growth in advanced stages of the disease. In this review article, we will explore possible causes underlying defects in angiogenic signaling in the hypertrophied heart resulting in a mismatch between cardiac oxygen needs and supply. Although myocardial ischemia also is associated with hypertrophy of the surviving myocardium, we will focus primarily on cardiac hypertrophy developing in response to increased pressure, but also volume overload.Heart failure is a major cause of morbidity and mortality affecting several million individuals worldwide. Left ventricular hypertrophy represents an adaptive response of the heart to an increased workload but is also a well-established risk factor for cardiovascular mortality  and may In humans and other mammalian species, the heart is perfused via the coronary circulation, in contrast to amphibians, in which the spongy heart musculature is lined by a thin monolayer of endothelial cells and directly perfused with blood from the ventricular cavity . During per se is associated with cardiac microvascular rarefaction as well as other important changes at the level of the terminal vascular bed, as shown in mice  and sedentary  animals, revealed that cardiac capillary density is inversely related to heart rate with high-frequency having a less dense capillary network . Brachyc to rats  was show to rats . The ang to rats , an impo to rats , 16. In  to rats . The pos to rats  might al to rats .Rapid heart growth is observed during early postnatal development, whereas later in life, myocardial hypertrophy develops as adaptive response of the heart to chronically increased workload in order to maintain cardiac output. Any increase in heart tissue must be matched by a corresponding expansion of the coronary vasculature to maintain an adequate supply of oxygen and nutrients. Short-term regulatory mechanisms activated by inadequate oxygenation include adenosine-induced vasodilation to maintain perfusion. If the stimulus persists, hypertrophied cardiomyocytes and other cell types in the heart secrete factors to stimulate the parallel growth of their supplying vascular network in order to meet the increased oxygen demands. Important angiogenic mediators in the heart will be discussed in one of the next sections.In cardiac hypertrophy developing in response to postnatal growth, physical exercise or pregnancy, so-called physiological hypertrophy, capillaries grow proportional to cardiomyocyte volume thus maintaining the capillary density observed in normal non-hypertrophied hearts. In contrast, maladaptive or pathological cardiac hypertrophy is characterized by an inadequate rarefaction of the cardiac microvasculature. Since cardiac perfusion and blood supply is critically determined on the level of the capillaries , any redChanges in the cardiac microvasculature during cardiac hypertrophy have been examined in a number of studies, for example in hypertrophic  and dilaThe reduction of myocardial blood flow due to left ventricular hypertrophy results in perfusion deficits and myocardial ischemia at times of elevated cardiac stress, in particular in the subendocardium, as shown in dogs , 30. AlrInterestingly, capillary density with left ventricular hypertrophy has been shown to depend on the age of onset. For example, vascular rarefaction was present in adults with acquired aortic stenosis, whereas capillaries were found to grow proportional to cardiomyocyte volume in patients with congenital aortic stenosis and aortic coarctation .2+ sensitivity  resulting in chronically increased pressure overload was associated with a reduced capillary density, whereas capillary angiogenesis was maintained in hearts exposed to volume overload induced by aortocaval shunt , 52 or cMicrovessel density in the heart is often quantified by counting the number of capillaries per cardiomyocyte fiber (C/F ratio) on transverse tissue sections. However, this methodology detects alterations in tissue oxygenation only if cardiomyocyte size does not change. In the case of cardiomyocyte hypertrophy, no changes in the C/F ratio would still result in an increased oxygen diffusion distance and possibly hypoxia. Measurement of the intercapillary distance may provide additional information. An additional means to assess cardiac vascularization is the quantification of the capillary density , although this method may be subject to technical variables . Image acquisition and analysis software may be used in addition to the manual quantification of vessel numbers to determine additional parameters, such as the average vessel length or diameter or the number and complexity of branch points, to better describe spatial vascular patterns in the heart. Platelet-endothelial cell adhesion molecule (PECAM or CD31) is a commonly used marker to stain endothelial cells and has the advantage that immature endothelial cells. i.e., the ones covering newly formed blood vessels, are also detected, while these might be missed if the tight junction protein VE-cadherin or the Weibel-Palade body component von Willebrand factor (vWF) are chosen as endothelial cell markers. However, it should be kept in mind that CD31 is also expressed on hematopoietic cells . StaininAs outlined above, capillary density is an important factor in the development of either physiological or pathological hypertrophy. But what are the factors regulating angiogenesis in the heart? In general, capillary perfusion, the length of the diastolic interval, and diastolic ventricular chamber filling provide initiating stimuli for capillary angiogenesis during cardiac enlargement . In addi164 and VEGF188 isoform exhibited impaired myocardial angiogenesis resulting in ischemic cardiomyopathy and heart failure  and receptor 2 (VEGFR2) expressed in the heart. Binding of VEGF to VEGFR1 leads to activation of cyclic guanosine monophosphate-dependent protein kinase-1 signaling pathways resulting in the formation of new blood vessels and regression of hypertrophy, whereas activation of VEGFR2 signaling results in cardiac hypertrophy . InteresOther miRNAs enriched in endothelial cells indirectly targeting VEGF and other angiogenic growth factors include miR-214 , 89 and Binding of VEGF and other growth factors signaling via tyrosine kinase receptors induces phosphorylation of protein kinase B (Akt), a major signaling pathway in the heart involved in the regulation of cardiac growth, contractile function and angiogenesis . In thisin vivo RNA interference against tissue inhibitor of matrix-metalloproteinases-3 , a member of the VEGF superfamily secreted by cardiomyocytes and cardiac microvascular endothelial cells. Similar to VEGF, PlGF expression in the heart is regulated by HIF1α  and induinases-3 . PlGF ovinases-3 . In addiinases-3 . Of noteinases-3 , 113.The expression of platelet-derived growth factors (PDGFs) is also markedly induced in the heart in response to load-induced stress , and stuThe PDGF family consists of four ligands (PDGF-A to PDGF-D), which bind to PDGF receptor (PDGFR)-α or -β isoforms. While PDGFRα binds to PDGF-A, -B, and -C chains, the β-isoform of PDGFR binds only to PDGF-B and PDGF-D . Endothein vitro after gain- and loss-of-function modulation of the myosin phosphatase-RhoA-interacting protein in pericytes  is also expressed in endothelial cells, including those in the heart, and has been shown to enhance myocardial collateral development in a canine model of coronary occlusion , 135. LaGrowth factors with potential angiogenic activities in the heart also include epidermal growth factor (EGF). Although earlier studies using rat heart endothelial cells revealed that EGF stimulated endothelial cells growth and colony formation , its conin vitro that HGF directly promotes endothelial cell proliferation and migration  and the tyrosine kinase receptor (c-Met) have also been implicated in myocardial function, both under physiological and pathological conditions . It has igration  and inhiigration  resultinigration  and skeligration . In addiigration  and promigration . HGF alsigration .Factors modulating cardiac angiogenesis are not only produced by cardiomyocytes, but may also be derived from immune cells, in particular monocytes, as shown in mice after acute myocardial infarction . FurtherIn addition to the transcriptional regulators ETS1, GATA2, and GATA4, mentioned above, other important factors controlling angiogenic gene transcription in endothelial cells include Kruppel-like factors (KLFs). The main KLFs expressed in endothelial cells are KLF2, 4, 6, and 15, which regulate the expression of a number of genes involved in endothelial cell homeostasis in response to changes in laminar blood flow, shear stress, or proinflammatory cytokines [reviewed in ]. KLF2 eCollectively, these data suggest a critical role of paracrine growth factors from cardiomyocytes and non-myocytes in modulating cardiac vascularization and the importance of a balanced cardiomyocyte and endothelial cell growth during cardiac hypertrophy. A schematic drawing depicting some of the changes during the development of cardiac hypertrophy is provided in Whereas, the role of VEGF and other angiogenic growth factors for cardiac angiogenesis has been intensively studied, the molecular mechanisms and mediators underlying the rarefaction of the cardiac microvasculature during pathological hypertrophy are less well-understood. The existing clinical and preclinical evidence suggests that they may include an insufficient vessel growth due to inadequate release of angiogenic growth factors from cardiomyocytes, platelets and inflammatory cells, impaired angiogenic signaling and the regression, or death of cardiac endothelial cells.ex vivo, pretreatment with pulsed magnetic field stimulation to increase endothelial VEGF and FGF2 secretion was successful to accelerate proliferation and migration of cardiac microvascular endothelial cells isolated from rat hearts  and the dephosphorylation of specific phosphotyrosine residues. In addition, PTPs may also control the phosphorylation state of intermediary signaling proteins involved in growth factor and integrin signaling, endothelial cell function and angiogenesis.A major PTP expressed in endothelial cells is Protein Tyrosine Phosphatase (PTP)-1B. PTP1B is overexpressed in human and murine heart failure: For example, a significantly increased PTP1B activity was detected in hypertrophic hearts of rats after bandings as well as in left ventricular tissue specimens of patients with systolic dysfunction undergoing aortic valve replacement , and we In line with the role of PTP1B as negative regulator of VEGFR2 autophosphorylation , we coulElevated levels of PTP1B have also been implicated in the pathophysiology of endothelial dysfunction. Not only may endothelial failure to vascularize the heart contribute to cardiac decompensation, but heart failure itself is associated with endothelial dysfunction. In this regard, pharmacological inhibition of PTP1B was shown to improve the peripheral endothelial dysfunction in mice with post-ischemic heart failure . EnhanceIn addition to VEGF receptors, other receptor tyrosine kinases expressed in the heart and regulated by PTP1B include receptors for PDGF, FGF, EGF, or HGF. PTP1B may also dephosphorylate Tie1 and Tie2, i.e., the receptors for angiopoietin-1 and -2, major angiogenic growth factors involved in vessel maturation and stabilization , althougA genome-wide gene expression analysis of mouse hearts revealed that increased cardiac afterload is associated with elevated expression of several counterregulatory phosphatases , includiin vitro reendothelialization. Replicative senescence and premature telomere shortening due to continuous receptor tyrosine kinase overstimulation may also have played a role, as shorter telomeres have been observed in leucocytes -collagen prolyl-4-hydroxylase gene resulting in the extracellular release of antiangiogenic fragments from collagen type 4 and 18 . Others The expression of angiogenic growth factors during cardiac hypertrophy may also be regulated on the level of chromatin structure and the acetylation of histone proteins  by either histone acetyl transferases (HATs) or histone deacetylases (HDACs) resulting in activation or inhibition of gene transcription, respectively. These and other mechanisms involved in the epigenetic control of gene expression in cardiac hypertrophy and heart failure have also been very clearly presented in a recent review article to which we refer for further details . In factOther mechanism involved in the regulation of angiogenic gene transcription and vascular development include chromatin remodeling enzymes, such as the ATPases Brahma-related gene-1 and Brahma  or Ino80Endothelial cells are not only important cellular mediators of cardiac vascularization, but are also actively involved in communicating with adjacent cardiomyocytes, fibroblasts and other cells resident in the heart by the release of growth factors, such as NO –280, endIn vivo, TGFβ1 released from activated platelets inhibited endothelial regeneration (Cardiac fibrosis is an important histological feature of pathological hypertrophy, and the accumulation of extracellular matrix proteins contributes to ventricular dilatation and contractile dysfunction. Mediators expressed at increased levels in hypertrophied hearts involved in fibroblast activation and cardiac fibrosis include aldosterone, angiotensin II, endothelin-1 as well as the growth factors TGFβ1, PDGFs, and connective tissue growth factor, among others . In addineration  and promneration , whereasneration , suggestNot only the amount, but also the composition of the extracellular matrix may play a role in the regulation of endothelial cell phenotypes, for example via interaction with integrins expressed on endothelial cells. Syndecan-4, a heparan sulfate-carrying core protein expressed in cardiomyocytes and present in the extracellular matrix of the heart, binds several growth factors, including FGF2. On the other hand, matrix-metalloproteinase or other proteases may release anti-angiogenic factors from extracellular matrix proteins and thus disturbed the balance of factors controlling vessel growth. Any changes in the composition developing during cardiac hypertrophy remodeling may alter angiogenic signaling and endothelial responsiveness and contribute to the functional and structural deterioration.During the past years, considerable knowledge has accumulated regarding the regulation of new vessel formation in the healthy and the hypertrophied heart. It has become clear that cardiac endothelial cells not only respond to hemodynamic forces and paracrine signals from neighboring cells, but also actively participate in cardiac remodeling processes by stimulating cardiomyocyte growth and contractility or the production of extracellular matrix proteins in myofibroblasts. Moreover, in response to adequate signals they may change their phenotype and transdifferentiate into extracellular matrix-producing cells. Because cardiac vascularization plays a central role in the transition from adaptive cardiac hypertrophy to heart failure, endothelial cells and signaling mechanisms involved in the regulation or dysregulation of angiogenesis in the heart represent promising therapeutic targets to improve pressure overload-induced cardiac remodeling and to prevent the transition to heart failure. However, potential treatment strategies are currently limited to the experimental, preclinical stage and have not entered the clinic.RG, MB, and KS wrote the manuscript. KS acquired funding. Authors have read and approved the final manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Histone deacetylase 6 (HDAC6), a cytoplasmic enzyme that plays important roles in many biological processes, is one isoform of a family of HDAC enzymes that catalyse the removal of functional acetyl groups from proteins. HDAC6 stands out from the other members of this family because it almost exclusively deacetylates cytoplasmic proteins and exerts deacetylation-independent effects, which has led to the successful development of relatively isoform-specific inhibitors of its enzymatic action. Numerous studies have recently demonstrated that HDAC6 expression and activity are increased in kidney disease, such as autosomal dominant polycystic kidney disease (ADPKD), renal fibrosis, and acute kidney injury (AKI), among others. Moreover, HDAC6 inhibitors have been investigated for use in treating these diseases. In fact, HDAC6 inhibitors effectively limit the progression of kidney diseases, suggesting that targeting HDAC6 may provide a novel treatment approach. However, the primary challenge in developing HDAC6-targeted therapies is understanding how the renoprotective effect of NDAC6 inhibitors can be selectively harnessed. Here, we discuss the unique function of HDAC6 and recapitulate the alluring potential of its inhibitors in kidney diseases. The halHDAC6 promotes cyst formation and disease by enhancing intracellular cAMP in ADPKD. Abnormal proliferation of the cyst-lined epithelium and increased intra-cystic fluid secretion via the cystic fibrosis transmembrane conductance regulator (CFTR) may contribute to cyst growth in ADPKD  activity , is the endpoint of chronic kidney disease. Connective tissue growth factor (CTGF), implicated in the formation of ECM, including the ECM proteins fibronectin and collagen, is considered to be a molecular hallmark of renal fibrosis  is an autoimmune disease in which the immune system produces autoantibodies against normal healthy tissue or cellular components to form immune complexes that are deposited in various tissues and subsequently induce inflammation, leading to tissue damage , which is characterized by a rapid decline in the glomerular filtration rate, is a serious clinical problem. AKI is not only associated with high rates of mortality but also an increased risk of chronic kidney disease (Geng et al. Inhibition of HDAC6 protects against ischaemic stroke and prolongs survival after sepsis in animal models (Wang et al. HDAC6 plays a aggravating role in kidney diseases, and up-regulation of HDAC6 could exacerbate kidney diseases. In ADPKD, a role of HDAC6 in cytogenesis has been identified, as HDAC6 facilitates the progression of ADPKD by regulating Ca2+ signalling, cAMP signalling and EGFR endocytic trafficking and degradation. Moreover, treatment of ADPKD with HDAC6 inhibitors is effective, suggesting that these molecules are promising drug candidates for alleviating ADPKD. Furthermore, HDAC6 is closely related to other kidney diseases, including LN and AKI. Given its function in immune responses, HADC6 may participate in the onset of primary MN; however, additional studies are needed to confirm this idea.


Recent research in the last decade has sought to explore the role and therapeutic potential of Liver X Receptors (LXRs) in the physiology and pathologies of the Peripheral Nervous System. LXRs have been shown to be important in maintaining the redox homeostasis in peripheral nerves for proper myelination, and they regulate ER stress in sensory neurons. Furthermore, LXR stimulation has a positive impact on abrogating the effects of diabetic peripheral neuropathy and obesity-induced allodynia in the Peripheral Nervous System (PNS). This review details these findings and addresses certain important questions that are yet to be answered. The potential roles of LXRs in different cells of the PNS are speculated based on existing knowledge. The review also aims to provide important perspectives for further research in elucidating the role of LXRs and assessing the potential of LXR based therapies to combat pathologies of the Peripheral Nervous System. Nr1h3 and Nr1h2, respectively. Although classified as orphan receptors upon discovery, oxidized cholesterol derivatives (oxysterols) such as 20(S)-, 22(R)-, 24(S)-, 25- and 27-hydroxy cholesterol (HC) and 24(S), 25-epoxycholesterols were later found to be their natural ligands [Liver X Receptors (LXRs) are ligand-activated transcription factors that exist in 2 isoforms: LXRα and LXRβ encoded in mice by the genes LXRs have been implicated in several physiological processes such as lipid metabolism and homeostasis, inflammation and cholesterol homeostasis, as well as a plethora of diseases such as Multiple sclerosis, Alzheimer’s, Arthritis, and cancers ,7,8,9,10The implications of LXRs in both the physiology and pathology of the Central Nervous System (CNS) have been extensively studied and reported over the last few years. Seminal and extensive reviews have diligently detailed almost every aspect of LXRs’ function in the brain from development to diseases ,13,14. TA holistic understanding—of the implications of LXRs and their natural ligands—elicits a clear division of the different components of the PNS. Each specific cell type of the PNS functions differently at a molecular level; making the fatty acids, and cholesterol metabolism in the spinal nerves can require highly diverse and cell-type-specific actions. Broadly, the PNS can be classified into the following cellular subtypes: Schwann cells, endoneurial cells, perineurial cells, sensory neurons   Figure .The somata of the motor neurons are located in the spinal cord, and only their axons form a part of the PNS. Hence, lipid and cholesterol metabolism, and possible implications of LXRs in motor neuron physiology and associated diseases falls beyond the ambit of this review but have been reviewed elsewhere ,17,18. I−/− hereafter referred to as LXR double KO or LXRdKO) [Schwann cells constitute a major portion of the spinal nerves and are by far the most extensively studied glial cells of the peripheral nervous system. They are directly responsible for the production of the myelin sheath around peripheral axons . The com LXRdKO) ,21,22.Mpz) and peripheral myelin protein 22 (Pmp22), observed through a promoter transactivation assay using constructs of both the myelin genes. Interestingly, in silico analysis revealed putative LXR response element (LXRE) sites upstream of these genes, and ChIP analyses confirmed that the stimulation of LXRs increased its occupancy at these sites. Moreover, LXR activation also downregulates key components of the Wnt/β Catenin pathway, an important driver of myelination and remyelination of peripheral nerves [The first study exploring oxysterol/LXR signaling in Schwann cells revealed that 3 oxysterols well known to be LXR ligands (namely 24(S)-, 25-, and 27-HC) and their corresponding biosynthetic enzymes are present in adult mouse sciatic nerves as well as in a mouse Schwann cell line (MSC80) . Treatmel nerves ,24.Mpz and Pmp22 were upregulated complementing the results observed in MSC80. However, their protein levels were significantly lower. Moreover, the animals displayed compact but thinner myelin sheaths, possibly due to a reduction of the myelin proteins that help in maintaining the structural integrity of the sheath [However, the observations in the sciatic nerve of LXRdKO animals were interestingly different. Firstly, the transcripts of e sheath . This ise sheath . This ph−/− and ATP Binding Cassette Transporter A1 (ABCA1)−/−, demonstrates a direct link between PMP22 and LXR target genes such as ATP Binding Cassette Transporter A1 (ABCA1) and Apolipoprotein E (ApoE) [−/− mutant Schwann cells was observed in culture along with an accumulation of lipid droplets and vesicles in mutant nerves. These observations were corroborated with a downregulation of certain genes implicated in the Sterol Regulatory Element Binding Protein (SREBP) pathway, notably Fatty Acid Synthase (FASN), HMG CoA reductase (HMGCR), and Low-Density Lipoprotein Receptor (LDLR), possibly because of a cellular response to halt lipogenesis and cholesterol synthesis following their accumulation. Targets of LXR such as ABCA1 and ApoE are possibly upregulated due to the accumulation of cholesterol as these genes are directly responsible for cholesterol efflux from the cell. However, the authors state that they do not see any modulation of LXRs in this phenomenon. The downregulation of the SREBP1c pathway, together with an upregulation of cholesterol efflux genes without any changes to LXR levels, presents a paradoxical situation as both these pathways are positively regulated by LXRs. The ABCA1−/− model, on the other hand, has a converse effect with respect to PMP22. While the accumulation of lipid droplets in these mutant nerves comes as no surprise, the authors also show an increase in PMP22 protein levels coupled with improper processing of de novo PMP22 synthesis. Intriguingly, this is in stark contrast to what is observed in an LXR deficient system where the protein levels of PMP22 are downregulated [A very recent study, using two different knockout mice models, PMP22E (ApoE) . Increasegulated ,22. FurtSrebf1) is a transcription factor that is located in the Endoplasmic Reticulum (ER) and shuttles to the nucleus upon activation (referred to as the active form). In STZ treated animals, ER retention was higher, and, upon LXR activation, there was an increase in nuclear translocation, thus resulting in the transcription of lipogenic genes and enzymes. They also show evidence of a restoration in MPZ protein levels, which was previously downregulated due to STZ treatment. This rescue at the molecular level also improves the myelin ultrastructure in the nerve. In another study, the authors also provide evidence of an increase in neurosteroid synthesis upon LXR activation [In a pathological context, LXR activation has proven to be beneficial as a therapeutic approach to alleviate structural and neurophysiological anomalies of Diabetic Peripheral Neuropathy (DPN) using two distinct pathways ,29. In ativation . Neurosttivation ,31,32. IThe physiological understanding of the role of LXRs in Schwann cell biology stems for animal models where both the isoforms of LXR are deleted systemically. Although studies point to the possible role of Schwann cells in the resulting phenotype, one cannot negate the impact and the contribution of other systems on the observed phenotype. A thorough understanding of the role of LXRs can be achieved using a Schwann cell-specific knock out. To date, only a few mutant models have targeted cholesterol and fatty acid metabolism in Schwann cells ,34,35. T−/− animals exhibit the exact opposite phenotype with accumulation of lipids and cholesterol in Schwann cells [Moreover, Schwann cell pathologies open up multiple avenues of research using LXRs. The intricate association between PMP22, LXRs, lipids, and cholesterol explained herein offer unexplored possibilities of using the LXR pathway therapeutically in the treatment of Charcot-Marie-Tooth 1A (CMT1A). CMT1A in humans is characterized by a duplication of Chromosome 17p12 (c17p12), which is a large segment of DNA that encodes the PMP22 protein ,37. Thisnn cells . In the nn cells . A similAnother Schwann cell pathology that is of particular interest to the glial research community is Malignant Peripheral Nerve Sheath Tumor (MPNST), a malignant form of Neurofibromatosis Type 1 (NF1) resulting from a loss of function mutation in the Neurofibromin 1 gene ,40. MPNSThe implications of LXRs in the pathophysiology of sensory neurons has recently been elucidated in two interesting studies ,50. In oAbca1 and Srebp1c in the nodose ganglia. Secondly, when these mutant mice were fed a western diet, they accumulated more cholesterol in the ganglia. However, they did not seem to gain more weight after western diet when compared to controls. This was coupled with lesser body fat accumulation and no difference in lean mass. Upon further inspection, it was revealed that mitochondrial metabolism was upregulated in the brown adipose tissue due to an upregulation of genes such as Uncoupling protein 1 (Ucp1) and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (Pgc1α) both at the transcript and protein levels. Additionally, mitochondrial oxidative respiration was also activated in the skeletal muscle. Thus, the authors postulated that the two observations correlate with the observed lack of weight gain in these mutants. Finally, the authors also observed a downregulation in γ synuclein (Syng) in the nodose ganglia, a protein that is known to regulate synaptic trafficking and the formation of lipid droplets. They remarked this down-regulation, and the observed phenotype concurs with the total Syng−/− mouse model and that the obesity-resistant phenotype is also observed in the LXRdKO mice. The study concluded that regulation of cholesterol and lipid metabolism can have post-synaptic effects in other tissues through yet undiscovered mechanisms.The second study was conducted in the nodose ganglia of the vagus nerve using the same cell-specific Nav1.8 Recombinase driver to ablate both LXRs. Nav1.8 sensory neurons are also situated in the nodose ganglia . This st−/− mice tend to show more pertinent phenotypes than LXRα−/− mice, possibly because of the distribution of their expression in different regions [Both these studies have been conducted in mice with cell-specific ablation of both LXRα and LXRβ. However, the first study does state that the expression levels of both these isoforms are not equal in the ganglia . LXRβ ex regions . SecondlEndoneurial cells  are multifaceted glial cells which are implicated in various functions such as endoneurial structural integrity, myelin clearance after nerve injury, as well as in mediating immune responses in the peripheral nerves ,52. The Firstly, endoneurial cells have been directly implicated in the clearance of myelin debris through phagocytosis ,55,56. TSecondly, endoneurial cells are also known to be the first immune responders during nerve injury and participate in creating a proinflammatory environment that favors myelin clearance and axonal regeneration . ConsequPerineurial cells are cells that align the perineurium of the spinal nerves. They were previously thought to have mesenchymal origins and, hence, were called perineurial fibroblasts . HoweverDhh in target cells. The activation of SMO, however, requires the presence of endogenous cholesterol or oxysterols, some of which are potent ligands of LXR [Interestingly, hedgehog signaling is intrinsically linked to cholesterol, both in the cells that secrete the protein as well as the ones receiving it . In the s of LXR ,67. TherThe review so far has considered the implications of LXRs in the physiology and pathology of the Peripheral Nervous System along with associated research questions that are yet to be answered. Cholesterol and lipid metabolism are fundamental biochemical processes that are essentially involved in most cell types of the body. Indeed, the different cells of the PNS utilize these metabolic processes, possibly by the same means, although for different ends. LXRs find themselves at the nexus of these two metabolic processes and, hence, understanding their physiological role in its entirety is crucial for formulating both cellular and generic therapeutic approaches. For instance, stimulating LXRs may render the desired effect of cholesterol efflux through ABCA1 and ApoE, but would also result in increasing lipogenesis through the SREBP pathway if the system permits both. This is one of the main reasons why administering LXR agonists as such as T0901317 or GW3965 for therapy might have the desired effects on the system being studied, but also promote dyslipidemia in the liver and reverse cholesterol transport systemically. Similarly, antagonizing or inhibiting LXRs could result in cholesterol accumulation and would concomitantly decrease lipogenesis in any system.Certain plausible solutions can be envisaged to tackle this conundrum and to make LXR based therapies more tenable. Fundamental research on identifying which isoform of LXR is necessary and sufficient for a physiological function provides a better framework for designing therapies using isoform-specific agonists or antagonists. For example, in the CNS, LXRβ is known to regulate Oligodendrocyte Precursor Cell (OPC) differentiation, prevent adult motor neuron degeneration, and promote ventral midbrain neurogenesis ,69,70. HAnother solution to make successful LXR based therapies is to identify function/cell-specific ligands without any prior knowledge of their specificity to different isoforms. This has been well elucidated in the case of macrophages where desmosterol has been shown to activate cholesterol efflux through LXR in these cells, but not induce lipogenesis in the hepatocytes ,76. IdenWith regard to human pathologies, stimulating LXRs seems to be a possible therapeutic approach for CMT1A. The objective of such an approach would be to counteract the phenotypic decrease in lipogenesis by stimulating the LXR/SREBP1c axis. For NF1 related MPNSTs, the potentiality of LXR based therapies can only be evaluated if the lipogenic role of the nuclear receptor is completely understood both in benign plexiform neurofibromas and MPNSTs. Nevertheless, as increased lipogenesis is a hallmark of MPNST, inhibiting LXRs can be envisaged as a plausible therapeutic approach.In conclusion, further research in the PNS should be directed towards understanding the role of LXRs at a cellular level in different glial cells of the PNS. Moreover, the identification of the functional isoform in each cell type would provide additional information in our understanding of PNS physiology. Fundamental research is also required in identifying local, tissue-specific natural agonists or antagonists of LXR. These advances would permit us to assess the true potential and promise of LXR based therapies for different pathologies of the PNS.