Biology subjects

Juskiewicz, Z. J.

Publications and source records attributed to Juskiewicz, Z. J..

3 recordsLinked to original sources

bioRxiv2026

Pannexin 1 phosphorylation sites differentially modulate channel activity and physiological outcomes

Within the vasculature, pannexin 1 (PANX1) channels in smooth muscle cells (SMCs) regulate -adrenergic constriction and blood pressure. PANX1 channel activity is regulated by phosphorylation at Y198, S205 and Y308 residues, but the physiological significance of these modifications is unknown. Here, we utilize newly developed PANX1 Y198F, S205A and Y308F phospho-dead mutant mice to test physiological changes related to hemodynamics. Radiotelemetry-measured blood pressure was decreased in Y198F, increased in Y308F, but unchanged in S205A mice at baseline. Clonidine-sensitive sympathetic-driven hypertension was observed in all mouse lines except Y198F. Pressure myography of third-order mesenteric arteries revealed -adrenergic contractile responses were decreased in Y198F, slightly enhanced in Y308F, but unchanged in S205A, with responses in Y198F vessels mimicking controls treated with PANX1 inhibitors. To understand signaling changes driving these phenotypes, we performed mesenteric artery bulk RNA sequencing, but found a minimal number of differentially expressed genes between phospho-dead mutants and controls. Similarly, co-immunoprecipitation-mass spectrometry of wildtype or phospho-dead mutant-expressing vascular SMCs revealed few interacting proteins distinct to each PANX1 variant. However, PANX1 channel activity assessments in HEK293T cells expressing the 1D-adrenergic receptor as well as each phospho-dead mutant PANX1 showed that phenylephrine-induced ATP release from Y198F channels was significantly decreased compared to wildtype, but current was unaffected. Conversely, basal and phenylephrine-induced S205A and Y308F currents were reduced, but ATP release resembled controls. Taken together, these findings indicate that distinct PANX1 phosphorylation determines PANX1 metabolite release versus current conducting properties and in turn, regulates physiological outcomes in the vasculature. One Sentence SummaryPANX1 Y198 phosphorylation-mediated ATP release is a major driver of -adrenergic vasoconstriction in vascular smooth muscle cells.

physiology↗

bioRxiv2025

Arterial iron regulates vasodilation during anemia via endothelial holo-alpha globin

Iron deficiency is a highly prevalent nutrient deficiency and the most common cause of anemia. Although iron deficiency exacerbates cardiovascular disease, the direct impact of iron deficiency on the vasculature remains unstudied. We assessed iron levels across the vascular endothelium and found resistance artery endothelial cells to have the lowest iron stores suggesting they may be especially impacted by iron deficiency. Anemia has previously been shown to increase arterial NO signaling in patients, and we have previously shown endothelial -globin (Hb) scavenges nitric oxide (NO) in the resistance artery endothelium. We hypothesize iron regulates vascular function through downregulation of endothelial Hb. To test this, we used a novel model of iron deficiency anemia (IDA). In female mice, IDA increased NO signaling which was rescued to control levels by repletion of vascular iron with ferric dextran. Despite being similarly anemic and having a similar reduction in Hb protein, there were no changes in NO signaling across groups in male mice. We further measured whether Hb was in its heme-bound (holo-Hb) or heme-free (apo-Hb) state and found males did not fully lose holo-Hb. Using endothelial specific Hb knockout mice, we show loss of endothelial Hb is necessary for increased NO signaling in IDA and for the rescue of NO signaling by ferric dextran in female mice. Altogether the data presented here demonstrate iron modulates endothelial NO signaling through the regulation of Hb.

physiology↗

bioRxiv2025

Hypoxia-Induced Metabolic Reprogramming and Markings of Cell Fate in Concentric Arterial Hypertrophy

Chronic inhibition of the renin-angiotensin system (RAS), while widely used to treat hypertension, can lead to an underrecognized form of vascular disease marked by concentric arteriolar and arterial hypertrophy (CAAH). Here, using two lineage-traced mouse models of genetic renin deletion and sustained RAS blockade, we uncover a pathogenic cascade initiated by renin-lineage cell fate reprogramming. Loss of endocrine identity and transformation of smooth muscle cells drives a shift toward a fibrotic, inflammatory, and secretory phenotype that remodels the extracellular matrix and promotes vascular thickening and luminal narrowing. Integrated transcriptomic, proteomic, and metabolomic profiling revealed a hypoxia-linked metabolic switch--characterized by succinate accumulation and NAD+ depletion--coupled to Hif activation and disease progression. We identify Cdh13 and collagens (including Col1a1 and Col12a1) as early urinary biomarkers and define a 10-gene molecular signature of CAAH with potential clinical application. These findings establish renin-lineage cell plasticity and metabolic dysfunction as central drivers of CAAH and nominate candidate biomarkers for early detection and therapeutic targeting in RAS-inhibited patients.

physiology↗