Biology subjects

Arndt, P.

Publications and source records attributed to Arndt, P..

3 recordsLinked to original sources

bioRxiv2024

Metabolic alterations drive inflammatory phenotypes in CHIP-associated heart failure

Mutations in DNA methyltransferase 3 alpha (DNMT3A) are the most frequent driver of clonal hematopoiesis of indeterminate potential (CHIP), and associated with higher risk of cardiovascular disease and pro-inflammatory activation of immune cells. Here, we investigated the mechanisms underlying DNMT3A CHIP-associated inflammatory phenotypes in macrophages. We show that monocytes of DNMT3A CHIP-driver mutation carriers are associated with DNA hypomethylation of succinate dehydrogenase A (SDHA) and an altered tricarboxylic acid cycle metabolite profile. Silencing of DNMT3A in monocytes increased SDHA and elevated mitochondria complex II activity. The secreted complex II product, malate, further increased inflammatory activation in wild type monocytes to further augment inflammation in a paracrine manner. Pharmacological inhibition of SDHA (using dimethyl malonate) in mice harboring DNMT3A mutations in hematopoietic stem cells ameliorated the inflammatory response and improved cardiac function after myocardial infarction. Thus, interfering with the altered metabolic state may provide a new therapeutic option to dampen inflammatory activation in DNMT3A CHIP carrying patients.

molecular biology↗

bioRxiv2024

Pericytes mediate neurovascular remodeling in chronic arterial hypertension

Chronic arterial hypertension restructures the vascular architecture of the brain, leading to a series of pathological responses that culminate in cerebral small vessel disease. Pericytes respond dynamically to vascular challenges; however, how they manifest under the continuous strain of hypertension has not been elucidated. Therefore, in this study, we characterized pericyte behavior alongside hypertensive states in the spontaneously hypertensive stroke-prone rat (SHRSP) model, emphasizing their phenotypic and metabolic transformation. Our results reveal an early transition in PDGFR{beta}+ pericytes toward increased NG2 and CD13 co-expressing subtypes, signaling enhanced pericyte reactivity in an effort to stabilize vascular structures and an inflammatory engagement within the vascular niche in response to hypertensive stress. Gene expression profiling of microvessels revealed altered expression within crucial pathways i.e., angiogenesis, blood-brain barrier integrity, hypoxia and inflammation. Furthermore, we detected that circulating extracellular vesicles from SHRSP alter pericyte mitochondrial membrane potential, highlighting their ability to transmit pathogenic signals that exacerbate vascular remodeling. Detailed metabolic analysis revealed a significant shift toward glycolytic metabolism in pericytes already in initial hypertension, alongside a dysregulation of ATP production pathways. These findings emphasize the transformative influence of hypertension on cerebral pericytes and the extensive consequences on cerebral vascular health.

neuroscience↗

bioRxiv2023

Spatio-temporal dynamics of microglia phenotype in human and murine cSVD: impact of acute and chronic hypertensive states

Vascular risk factors such as chronic hypertension are well established major modifiable factors for the development of cerebral small vessel disease (cSVD). In the present study, our focus was the investigation of cSVD-related phenotypic changes in microglia in human disease and in the spontaneously hypertensive stroke-prone rat (SHRSP) model of cSVD. Our examination of cortical microglia in human post-mortem cSVD cortical tissue revealed distinct morphological microglial features specific to cSVD. We identified enlarged somata, an increase in the territory occupied by thickened microglial processes, and an expansion in the number of vascular-associated microglia. In parallel, we characterized microglia in a rodent model of hypertensive cSVD along different durations of arterial hypertension, i.e., early chronic and late chronic hypertension. Microglial somata were already enlarged in early hypertension, whereas at late-stage chronic hypertension they further exhibited elongat ed branches, thickened processes, and a reduced ramification index, mirroring the findings in human cSVD. An unbiased multidimensional flow cytometric analysis revealed phenotypic heterogeneit y among microglia cells within the hippocampus and cortex. At early-stage hypertension, hippocampal microglia exhibited upregulated CD11b/c, P2Y12R, CD200R, and CD86 surface markers. Detailed analysis of cell subpopulations revealed a unique microglial subset expressing CD11b/c, CD163, and CD86 exclusively in early hypertension. Notably, even at early-stage hypertension, microglia displayed a higher association with cerebral blood vessels. We identified several profound clusters of microglia expressing distinct marker profiles at late chronic hypertensive states. We further detected a temporal hypertension-related disturbances in blood-brain barrier integrity, accompanied by increased recruitment of leukocytes to the brain parenchyma in early hypertension. In summary, our findings demonstrate a higher vulnerability of the hippocampus, stage-specific microglial signatures based on morphological features, and cell surface protein expression in response to chronic arterial hypertension. These results indicate the diversity within microglia sub-populations and implicate the subtle involvement of microglia in cSVD pathogenesis.

neuroscience↗