Biology subjects

Gonzales, A. L.

Publications and source records attributed to Gonzales, A. L..

3 recordsLinked to original sources

bioRxiv2025

Increases in Plasma Viscosity Disrupt Microvascular Flow Dynamics

BackgroundAutoregulation of blood flow depends on pressure induced constriction and flow mediated dilation. These processes are well defined in arterioles, but how blood enters and distributes within the capillary network, the primary site of oxygen and nutrient exchange, is less understood. Endothelial cells and pericytes are increasingly recognized as active regulators of capillary tone, yet the mechanisms governing capillary level autoregulation remain unclear. Plasma viscosity is a major determinant of shear stress and may influence this regulation, but its role is not fully defined. MethodsUsing an ex vivo pressurized retinal preparation that preserves the arteriole to capillary continuum, we examined how changes in intraluminal viscosity and shear stress affect endothelial and mural cell activity during pressure driven flow. To study chronic viscosity elevation, we assessed microvascular structure, remodeling, endothelial responsiveness, and capillary perfusion in a high fat diet model of altered blood rheology. ResultsIncreasing viscosity enhanced endothelial Ca2+ activity in transitional and capillary segments and suppressed pressure induced Ca2+ elevations in smooth muscle cells and pericytes through nitric oxide dependent inhibition. Chronic elevation of viscosity produced segment specific effects. Arterioles showed structural remodeling and higher tone, whereas transitional and capillary vessels did not remodel and instead exhibited impaired endothelial shear sensing and reduced capillary recruitment. High fat diet feeding lowered baseline capillary perfusion and eliminated viscosity dependent modulation, indicating loss of shear-based control. ConclusionsAutoregulation differs fundamentally between arterioles and capillaries, and viscosity dependent endothelial signaling is a key determinant of capillary entry and flow distribution. Plasma viscosity is an important regulator of microvascular perfusion and a potential biomarker and therapeutic target in microvascular disease.

physiology↗

bioRxiv2024

Mitochondrial small RNA alterations associated with increased lysosome activity in an Alzheimer's Disease Mouse Model uncovered by PANDORA-seq

Emerging small noncoding RNAs (sncRNAs), including tRNA-derived small RNAs (tsRNAs) and rRNA-derived small RNAs (rsRNAs), are critical in various biological processes, such as neurological diseases. Traditional sncRNA-sequencing (seq) protocols often miss these sncRNAs due to their modifications, such as internal and terminal modifications, that can interfere with sequencing. We recently developed panoramic RNA display by overcoming RNA modification aborted sequencing (PANDORA-seq), a method enabling comprehensive detection of modified sncRNAs by overcoming the RNA modifications. Using PANDORA-seq, we revealed a novel sncRNA profile enriched by tsRNAs/rsRNAs in the mouse prefrontal cortex and found a significant downregulation of mitochondrial tsRNAs and rsRNAs in an Alzheimers disease (AD) mouse model compared to wild-type controls, while this pattern is not present in the genomic tsRNAs and rsRNAs. Moreover, our integrated analysis of gene expression and sncRNA profiles reveals that those downregulated mitochondrial sncRNAs negatively correlate with enhanced lysosomal activity, suggesting a crucial interplay between mitochondrial RNA dynamics and lysosomal function in AD. Given the versatile tsRNA/tsRNA molecular actions in cellular regulation, our data provide insights for future mechanistic study of AD with potential therapeutic strategies. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=120 SRC="FIGDIR/small/619155v1_ufig1.gif" ALT="Figure 1"> View larger version (31K): org.highwire.dtl.DTLVardef@1b6308borg.highwire.dtl.DTLVardef@2d02ddorg.highwire.dtl.DTLVardef@116ff5corg.highwire.dtl.DTLVardef@d7136d_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2021

Peripheral Coupling Sites Formed by STIM1 Govern the Contractility of Vascular Smooth Muscle Cells

Peripheral coupling between the sarcoplasmic reticulum (SR) and plasma membrane (PM) forms signaling complexes that regulate the membrane potential and contractility of vascular smooth muscle cells (VSMCs), although the mechanisms responsible for these membrane interactions are poorly understood. In many cells, STIM1 (stromal-interaction molecule 1), a single transmembrane-domain protein that resides in the endoplasmic reticulum (ER), transiently moves to ER-PM junctions in response to depletion of ER Ca2+ stores and initiates store-operated Ca2+ entry (SOCE). Fully differentiated VSMCs express STIM1 but exhibit only marginal SOCE activity. We hypothesized that STIM1 is constitutively active in contractile VSMCs and maintains peripheral coupling. In support of this concept, we found that the number and size of SR-PM interacting sites were decreased and SR-dependent Ca2+ signaling processes were disrupted in freshly isolated cerebral artery SMCs from tamoxifen-inducible, SMC-specific STIM1-knockout (Stim1-smKO) mice. VSMCs from Stim1-smKO mice also exhibited a reduction in nanoscale colocalization between Ca2+-release sites on the SR and Ca2+-activated ion channels on the PM, accompanied by diminished channel activity. Stim1-smKO mice were hypotensive and resistance arteries isolated from them displayed blunted contractility. These data suggest that STIM1 - independent of SR Ca2+ store depletion - is critically important for stable peripheral coupling in contractile VSMCs.

physiology↗