Biology subjects

Palzkill, V.

Publications and source records attributed to Palzkill, V..

3 recordsLinked to original sources

bioRxiv2023

Activation of the Aryl Hydrocarbon Receptor in Endothelial Cells Impairs Ischemic Angiogenesis in Chronic Kidney Disease

RationaleChronic kidney disease (CKD) is a strong risk factor for peripheral artery disease (PAD) that is associated with worsened clinical outcomes. CKD leads to accumulation of tryptophan metabolites that associate with adverse limb events in PAD and are ligands of the aryl hydrocarbon receptor (AHR) which may regulate ischemic angiogenesis. ObjectivesTo test if endothelial cell-specific deletion of the AHR (AHRecKO) alters ischemic angiogenesis and limb function in mice with CKD subjected to femoral artery ligation. FindingsMale AHRecKO mice with CKD displayed better limb perfusion recovery and enhanced ischemic angiogenesis compared to wildtype mice with CKD. However, the improved limb perfusion did not result in better muscle performance. In contrast to male mice, deletion of the AHR in female mice with CKD had no impact on perfusion recovery or angiogenesis. Using primary endothelial cells from male and female mice, treatment with indoxyl sulfate uncovered sex-dependent differences in AHR activating potential and RNA sequencing revealed wide ranging sex-differences in angiogenic signaling pathways. ConclusionEndothelium-specific deletion of the AHR improved ischemic angiogenesis in male, but not female, mice with CKD. There are sex- dependent differences in Ahr activating potential within endothelial cells that are independent of sex hormones.

physiology↗

bioRxiv2023

Single Nuclei RNA Sequencing of the Gastrocnemius Muscle in Peripheral Artery Disease

BackgroundLower extremity peripheral artery disease (PAD) is a growing epidemic with limited effecOve treatment options. Herein, we provide a single nuclei atlas of PAD limb muscle to facilitate a better understanding of the composition of cells and transcriptional differences that comprise the diseased limb muscle. MethodsWe obtained gastrocnemius muscle specimens from 20 PAD patients and 12 non-PAD controls. Nuclei were isolated and single nuclei RNA sequencing (snRNAseq) was performed. The composition of nuclei was characterized by iteraOve clustering via principal component analysis, differenOal expression analysis, and the use of known marker genes. BioinformaOcs analysis was performed to determine differences in gene expression between PAD and non-PAD nuclei, as well as subsequent analysis of intercellular signaling networks. Additional histological analyses of muscle specimens accompany the snRNAseq atlas. ResultssnRNAseq analysis indicated a fiber type shim with PAD paOents having fewer Type I (slow/oxidaOve) and more Type II (fast/glycolyOc) myonuclei compared to non-PAD, which was confirmed using immunostaining of muscle specimens. Myonuclei from PAD displayed global upregulation of genes involved in stress response, autophagy, hypoxia, and atrophy. Subclustering of myonuclei also idenOfied populations that were unique to PAD muscle characterized by metabolic dysregulation. PAD muscles also displayed unique transcriptional profiles and increased diversity of transcriptomes in muscle stem cells, regeneraOng myonuclei, and fibro-adipogenic progenitor (FAPs) cells. Analysis of intercellular communication networks revealed FAPs as a major signaling hub in PAD muscle, as well as deficiencies in angiogenic and bone morphogeneOc protein signaling which may contribute to poor limb function in PAD. ConclusionsThis reference snRNAseq atlas provides a comprehensive analysis of the cell composition, transcriptional signature, and intercellular communication pathways that are altered in the PAD condition.

genomics↗

bioRxiv2023

Chronic activation of the aryl hydrocarbon receptor in muscle exacerbates ischemic pathology in chronic kidney disease

Chronic kidney disease (CKD) accelerates the development of atherosclerosis, decreases muscle function, and increases the risk of amputation or death in patients with peripheral artery disease (PAD). However, the cellular and physiological mechanisms underlying this pathobiology are ill-defined. Recent work has indicated that tryptophan-derived uremic toxins, many of which are ligands for the aryl hydrocarbon receptor (AHR), are associated with adverse limb outcomes in PAD. We hypothesized that chronic AHR activation, driven by the accumulation of tryptophan-derived uremic metabolites, may mediate the myopathic condition in the presence of CKD and PAD. Both PAD patients with CKD and mice with CKD subjected to femoral artery ligation (FAL) displayed significantly higher mRNA expression of classical AHR-dependent genes (Cyp1a1, Cyp1b1, and Aldh3a1) when compared to either muscle from the PAD condition with normal renal function (P<0.05 for all three genes) or non-ischemic controls. Skeletal-muscle-specific AHR deletion in mice (AHRmKO) significantly improved limb muscle perfusion recovery and arteriogenesis, preserved vasculogenic paracrine signaling from myofibers, increased muscle mass and contractile function, as well as enhanced mitochondrial oxidative phosphorylation and respiratory capacity in an experimental model of PAD/CKD. Moreover, viral-mediated skeletal muscle-specific expression of a constitutively active AHR in mice with normal kidney function exacerbated the ischemic myopathy evidenced by smaller muscle masses, reduced contractile function, histopathology, altered vasculogenic signaling, and lower mitochondrial respiratory function. These findings establish chronic AHR activation in muscle as a pivotal regulator of the ischemic limb pathology in PAD. Further, the totality of the results provide support for testing of clinical interventions that diminish AHR signaling in these conditions.

physiology↗