Biology subjects

Davis, G. E.

Publications and source records attributed to Davis, G. E..

6 recordsLinked to original sources

bioRxiv2025

TNFα and Endothelial IL-1 Receptor Signaling Drive Peritubular Capillary Regression and Fibrosis in Obstructive Kidney Injury

Capillary regression destabilizes tissue homeostasis and contributes to chronic organ dysfunction, yet the inflammatory pathways that drive pathological vessel loss remain incompletely defined. We previously identified the inflammatory cytokines TNF and IL-1 as conserved mediators of physiological vessel regression in the neonatal mouse eye, but whether these cytokines contribute to pathological capillary regression in adult mice is unknown. In this study, we investigated the capillary regression that occurs along with inflammation in murine kidneys following irreversible unilateral ureteral obstruction (UUO) surgical challenge. Mice lacking genes encoding global TNF, the endothelial IL-1 receptor IL-1R1, or both (double knockout, DKO) were examined at 10 days after UUO surgery. While loss of the individual genes did not affect peritubular capillary (PTC) regression, PTC regression was significantly reduced in DKO mice. This reduction in PTC regression correlated with less expression of the tubular epithelial injury marker KIM-1. DKO kidneys also displayed less fibrosis by Picrosirius Red and Massons trichrome staining. These findings demonstrate that TNF and endothelial IL-1R1 cooperatively drive pathological capillary regression in the irreversible UUO model of chronic kidney injury and that preservation of PTCs correlates with less renal tubular injury and fibrosis at 10 days after injury. NEW & NOTEWORTHYPathological PTC regression drives progressive kidney injury, but its inflammatory triggers are unclear. Using the UUO model, this study identifies cooperative TNF and endothelial IL-1R1 signaling as key drivers of capillary loss. While deletion of either pathway alone was insufficient, combined loss preserved PTCs, reduced tubular injury, and attenuated fibrosis. These findings highlight synergistic inflammatory signaling in microvascular loss and suggest dual targeting may help preserve PTC integrity in chronic kidney disease.

pathology↗

bioRxiv2025

Big Data, Sound Science, Lasting Impact: a framework for passive acoustic monitoring

Marine passive acoustic monitoring (PAM) has produced petabytes of data that are used by researchers, resource managers, industry, and regulators to understand how marine animals use sound and the impacts of anthropogenic noise on species and ecosystems throughout the global ocean. These big data provide unprecedented opportunities to study underwater soundscapes and marine ecology but also enormous challenges to efficiently extract information. To address these challenges, a U.S. federally funded and led Sound Cooperative (SoundCoop) project built community-focused cyberinfrastructure to promote improved, scalable and sustainable processing and access of marine PAM data for management, science, industry and military applications. Driven by cross-institutional participation representing a diversity of data collection methods and conditions, the SoundCoop project established guidance for standardized processing of ocean sound level metrics using freeware software toolkits and developed core tools and processes that support open science. Four examples of comparative analyses that connect disparate PAM monitoring efforts, and integrate non-acoustic data illustrate how comparable, interoperable sound level metrics support a more coherent and synoptic perspective on global ocean soundscapes using methods that current and future PAM projects can leverage. Such a framework around PAM big data offers the opportunity to revolutionize large-scale marine ecology and oceanography in similar ways to other transformative approaches for understanding environmental or ecological patterns and processes at global scales.

ecology↗

bioRxiv2025

Lymphatic Malformations with Activating KRAS Mutations Impair Lymphatic Valve Development Through Matrix Metalloproteinases

BACKGROUNDLymphatic malformations (LMs) are lesions due to inherited or somatic mutations that lead to a defective lymphatic vasculature. Activating KRAS mutations have been identified recently in LM patients with lymphedema, chylous ascites, or life-threatening chylothorax. In a LM mouse model, KRAS mutations are associated with a loss of lymphatic valves, which has been proposed to cause chylothorax via retrograde lymph flow into the pleural space. However, the mechanisms underlying the loss of lymphatic valves are unknown. METHODSTo investigate the mechanisms leading to valve loss, we combined the lymphatic-specific and tamoxifen-inducible Flt4CreERT2 with Kras-loxP-stop-loxP-G12D (Kras+/G12D) mice and Prox1GFP reporter mice to induce the restricted expression of KRAS-G12D and enable valve quantification in postnatal pups. Human dermal lymphatic endothelial cells (hdLECs) expressing KRAS-G12D were probed for changes in mRNA and protein expression with qRT-PCR, western blot, and gel zymography, and mechanistic studies were performed using 3D cell culture in collagen matrices. RESULTSOur data showed that lymphatic-specific expression of KRAS-G12D significantly attenuated valve development in the mesentery, diaphragm, and ear skin. qRT-PCR, western blot, and gel zymography using hdLECs expressing KRAS-G12D revealed the upregulation of the plasminogen activator (PA) pathway and matrix metalloproteinases (MMPs). The MMPs were sufficiently activated by plasmin, the product of the PA pathway, in hdLECs grown in a 3D collagen matrix, indicating a role for MMPs in the degradation of valve ECM core. Furthermore, a broad-spectrum MMP inhibitor given to Flt4CreERT2;Kras+/G12D mice rescued lymphatic valve development. CONCLUSIONSWe conclude that hyperactive KRAS signaling upregulates MMPs that become excessively activated by the upregulation of the PA pathway. MMPs then degrade the lymphatic valve ECM core preventing valve formation.

pathology↗

bioRxiv2024

Lats1/2 are essential for developmental vascular remodeling and biomechanical adaptation to shear stress

Blood vessels in mammalian embryos develop from initial aggregates of endothelial cell (EC) progenitors, which coordinate the opening and stabilization of central vascular lumens, all while under progressively increasing flow and pressure from blood circulation. Mechanical cues exerted by shear stress from the blood flow remodel an initial vascular plexus into a ramifying array of large and small vessels. As plasma starts to fill vascular lumens, these forces trigger changes in EC gene expression and dynamic alterations in cell shape and cell adhesion, as cuboidal angioblasts elongate and flatten into ECs. Little is known about how embryonic ECs sense and transduce hemodynamic signals as vessels form in vivo. Here, we report a critical requirement for the Lats1 and Lats2 Hippo pathway kinases during this process. We show that when Lats1/2 are genetically deleted in ECs, embryos develop severe defects in blood vessel formation, which lead to embryonic lethality by E11.5. We find that initial vessel patterning and circulation initiate properly, however remodeling of the initial vascular plexus fails due to lumen collapse and altered blood flow. When Lats1/2 are knocked down using siRNA approaches in cultured ECs, cells fail to elongate and polarize, similar to ECs in the mutant embryos. In addition, VE-cadherin (VEcad) based junctions fail to mature under shear stress. These data show that Lats1/2 deficient cells no longer respond to laminar shear stress, both in vivo and in vitro. This work identifies the Hippo pathway kinases Lats1 and Lats2 as critical transducers of biomechanical cues during the early steps of blood vessel remodeling. This study will provide new targets for treatment of vascular diseases and new directions for efforts to generate vascularized tissues for replacement therapies. HighlightsO_LILats1 and Lats2 mRNA and protein are expressed in murine embryonic endothelial cells (ECs). C_LIO_LIDeletion of Lats1/2 in embryonic endothelium results in severe vascular defects and embryonic lethality. C_LIO_LILoss of Lats1/2 leads to failure of both vascular remodeling and EC elongation upon exposure to flow, in vivo and in vitro. C_LIO_LILats1/2 are required for cell-cell VE-cadherin adhesion maturation under flow. C_LIO_LILoss of Lats1/2 results in cytoskeletal disorganization in response to shear stress. C_LI

developmental biology↗

bioRxiv2023

SH2 domain protein E (SHE) and ABL signaling regulate blood vessel size

Blood vessels in different vascular beds vary in lumen diameter, which is essential for their function and fluid flow along the vascular network. Molecular mechanisms involved in the formation of a vascular lumen of appropriate size, or tubulogenesis, are still only partially understood. Src homology 2 domain containing E (She) protein was previously identified in a screen for proteins that interact with Abelson (Abl)-kinase. However, its biological role has remained unknown. Here we demonstrate that She and Abl signaling regulate vascular lumen size in zebrafish embryos and human endothelial cell culture. Zebrafish she mutants displayed increased endothelial cell number and enlarged lumen size of the dorsal aorta (DA) and defects in blood flow. Vascular endothelial specific overexpression of she resulted in a reduced diameter of the DA lumen, which correlated with the reduced arterial cell number and lower endothelial cell proliferation. Chemical inhibition of Abl signaling in zebrafish embryos caused a similar reduction in the DA diameter and alleviated the she mutant phenotype, suggesting that She acts as a negative regulator of Abl signaling. Enlargement of the DA lumen in she mutants correlated with an increased endothelial expression of claudin 5a and 5b (cldn5a / cldn5b), which encode proteins enriched in tight junctions. Inhibition of cldn5a expression partially rescued the enlarged DA in she mutants, suggesting that She regulates DA lumen size, in part, by promoting cldn5a expression. SHE knockdown in human endothelial umbilical vein cells resulted in a similar increase in the diameter of vascular tubes, and also increased phosphorylation of a known ABL downstream effector CRKL. These results argue that SHE functions as an evolutionarily conserved inhibitor of ABL signaling and regulates lumen size during vascular tubulogenesis.

developmental biology↗

bioRxiv2018

Anti-angiogenic effects of VEGF stimulation on endothelium deficient in phosphoinositide recycling

Anti-angiogenic therapies have generated significant interest for their potential to combat tumor growth (1-6). However, the ability of tumors to overproduce pro-angiogenic ligands and overcome targeted inhibitory therapies has hampered this approach (7, 8). A novel way to circumvent this problem might be to target the resynthesis of critical substrates consumed during intracellular transduction of pro-angiogenic signals in endothelial cells, thus harnessing the tumors own production of excess stimulatory ligands to deplete adjacent host endothelial cells of the capacity to respond to these signals (9-12). Here we show using zebrafish and human endothelial cells in vitro that endothelial cells deficient in CDP-diacylglycerol synthase 2 are uniquely sensitive to increased VEGF stimulation due to a reduced capacity to re-synthesize phosphoinositides, including phosphatidylinositol 4,5-bisphosphate (PIP2) a key substrate for VEGF signal transduction, resulting in VEGF-exacerbated defects in angiogenesis and angiogenic signaling (9-22). Using murine tumor allograft models (23) we show that either systemic or endothelial cell specific suppression of phosphoinositide recycling results in reduced tumor growth and reduced tumor angiogenesis. Our results suggest that inhibition of phosphoinositide recycling may provide a useful anti-angiogenic approach, and highlights the general potential of targeting the resynthesis of rate limiting signaling substrates as a valuable therapeutic strategy.\n\nSUMMARY STATEMENTTargeting phosphoinositide recycling during tumor angiogenesis provides a potentially uniquely effective anti-cancer therapy.

cell biology↗