Biology subjects

Meadows, S.

Publications and source records attributed to Meadows, S..

4 recordsLinked to original sources

bioRxiv2026

PRINCIPLES GOVERNING ENDOTHELIAL CAVEOLAE ORGANIZATION DURING ANGIOGENESIS

Caveolae, flask-shaped membrane invaginations highly enriched in endothelial cells, play a central role in buffering membrane tension, yet the principles governing their spatial organization remain elusive. This investigation sought to generate the most comprehensive and systematic analysis of blood vessel caveolar spatial organization. To do so, our group leveraged micropatterning technologies to impose precise biophysical constraints on endothelial cell geometry to probe how caveolae are organized under defined tensional and polarity environments. These experiments were integrated with a high-throughput spatial cell mapping computational pipeline for analyzing thousands of caveolae, providing an extremely high-fidelity analysis. Our results provide a governing framework of how total cellular caveolae are spatially organized during random and directional migration, non-motile polarized, nascent and stable monolayers with differing confinement levels as well as in angiogenic vasculature in vivo. Broadly, our results demonstrated caveolae preferentially organized in the rear of migrating and polarized endothelial cells. In differing monolayer configurations, caveolae default to a peri-junctional spatial organization. Lastly, in mouse retinal blood vessels caveolae are most prominent in the vascular front due to their responsiveness to vascular endothelial growth factor signaling. Overall, these results strongly suggest that caveolae cellular arrangement and number are highly predictive of vascular stability and remodeling states.

cell biology↗

bioRxiv2024

Endothelial Zmiz1 modulates physiological and pathophysiological angiogenesis during retinal development

Angiogenesis is a highly coordinated process involving the control of various endothelial cell behaviors. Mechanisms for transcription factor involvement in the regulation of endothelial cell dynamics and angiogenesis have become better understood, however much remains unknown, especially the role of non-DNA binding transcriptional cofactors. Here, we show that Zmiz1, a transcription cofactor, is enriched in the endothelium and critical for embryonic vascular development, postnatal retinal angiogenesis, and pathological angiogenesis in oxygen induced retinopathy (OIR). In mice, endothelial cell-specific deletion of Zmiz1 during embryogenesis led to lethality due to abnormal angiogenesis and vascular defects. Inducible endothelial cell-specific ablation of Zmiz1 postnatally resulted in impaired retinal vascular outgrowth, decreased vascular density, and increased vessel regression. In addition, angiogenic sprouting in the superficial and deep layers of the retina was markedly reduced. Correspondingly, vascular sprouting in fibrin bead assays was significantly reduced in the absence of Zmiz1, while further in vitro and in vivo evidence also suggested deficits in EC migration. In agreement with the defective sprouting angiogenesis phenotype, gene expression analysis of isolated retinal endothelial cells revealed downregulation of tip-cell enriched genes upon inactivation of Zmiz1. Lastly, our study suggested that endothelial Zmiz1 is critical for intraretinal revascularization following hypoxia exposure in the OIR model. Taken together, these findings begin to define the previously unspecified role of endothelial Zmiz1 in physiological and pathological angiogenesis.

developmental biology↗

bioRxiv2019

Branched photoswitchable tethered ligands enable ultra-efficient optical control and detection of class C G protein-coupled receptors

The limitations of classical, soluble drugs in terms of subtype-specificity, spatiotemporal precision, and genetic targeting have spurred the development of advanced pharmacological techniques, including the use of covalently-tethered photoswitchable ligands. However, a major shortcoming of tethered photopharmacology is the inability to obtain optical control with a comparable efficacy to the native ligand. To overcome the limitations of photoisomerization efficiency and tethered ligand affinity, we have developed a family of branched photoswitchable compounds to target G protein-coupled metabotropic glutamate receptors (mGluRs). These compounds permit photo-agonism of Gi/o-coupled group II mGluRs with near-complete efficiency relative to saturating glutamate when attached to receptors via a range of orthogonal, multiplexable modalities including SNAP-, CLIP-, and Halo-tags, as well as via receptor-targeting nanobodies. Through a chimeric approach, branched ligands also allow efficient optical control of Gq-coupled mGluR5 with precise, dynamic subcellular targeting. Finally, branched ligands enabled the development of dual photoswitch-fluorophore compounds that allow simultaneous imaging and manipulation of receptors via the same attachment point. Together this work provides a new design framework for photoswitchable ligands and demonstrates a toolset suitable for quantitative, mechanistic study of neuromodulatory receptors at the molecular, cellular and circuit levels.

bioengineering↗

bioRxiv2018

Dynamics of microRNA expression during mouse prenatal development

MicroRNAs (miRNAs) play a critical role as post-transcriptional regulators of gene expression. The ENCODE project profiled the expression of miRNAs in a comprehensive set of tissues during a time-course of mouse embryonic development and captured the expression dynamics of 785 miRNAs. We found distinct tissue and developmental stage specific miRNA expression clusters, with an overall pattern of increasing tissue specific expression as development proceeds. Comparative analysis of conserved miRNAs in mouse and human revealed stronger clustering of expression patterns by tissue types rather than by species. An analysis of messenger RNA gene expression clusters compared with miRNA expression clusters identifies the potential role of specific miRNA expression clusters in suppressing the expression of mRNAs specific to other developmental programs in the tissue where these microRNAs are expressed during embryonic development. Our results provide the most comprehensive timecourse of miRNA expression as an integrated part of the ENCODE reference dataset for mouse embryonic development.

genomics↗