Biology subjects

Shindo, A.

Publications and source records attributed to Shindo, A..

7 recordsLinked to original sources

bioRxiv2026

Dysregulated flow responses drive pathogenesis in a cellular model of Sturge-Weber syndrome

Vascular diseases comprise a broad spectrum of conditions associated with organ dysfunction, yet how endothelial responses to mechanical forces drive their pathogenesis remains unclear. Sturge-Weber syndrome (SWS), a flow-associated vascular malformation caused by somatic GNAQ mutations, provides a model to investigate this question. Here, using isogenic induced pluripotent stem cell-derived endothelial cells (ECs), perfusable vascular models, and simplified systems under defined flow conditions, we show that SWS ECs exhibited maladaptive responses to laminar flow, including impaired flow alignment, reduced CLDN5 expression, and decreased transendothelial electrical resistance. Importantly, three-dimensional acoustic microscopy uncovered disturbed surface changes in SWS ECs, potentially contributing to changes in mechanosensing signaling. Transcriptomic and chromatin accessibility analyses revealed dysregulated flow-responsive gene programs, some of which were validated in human SWS samples. These findings provide insights into flow-dependent endothelial dysfunction and a framework for therapeutic modulation in SWS and other vascular disorders.

cell biology↗

bioRxiv2026

Compartment-resolved in vivo phage display biopanning reveals constraint-driven peptide sequence landscapes

Previous in vivo phage display studies establish the value of the approach for identifying organ-homing and tissue-associated peptides, but whether recovered sequences form diffuse hit lists or structured repertoires remains unclear. This study combines systemic in vivo phage selection, laser-capture microdissection, and high-throughput sequencing to profile recoverable 7-mer peptide repertoires across 41 bulk organs, 39 capillary beds, and 125 parenchymal microenvironments. Across these anatomical scales, the repertoires show non-diffuse, compartment-dependent organization in enrichment-profile space, supported by robustness and null-model analyses. Compartment resolution provides information not apparent in bulk-organ profiles: representative motif-defined neighborhoods exhibit contrasting local sequence-tolerance regimes, ranging from bounded variation to near-single-sequence convergence. Compartment-resolved analysis also nominates EVGTARY, a cortex-associated candidate that is not prioritized by bulk-organ ranking. In an exploratory mouse-level analysis, an EVGTARY-conjugated branched polyethyleneimine (BPEI) polyplex is associated with increased cortical DsRed fluorescence compared with BPEI polyplex alone. Together, these findings shift the analytical unit of in vivo phage display from isolated organ-associated hits toward the organization of recoverable peptide repertoires and support an interpretation in which intact tissue context constrains the range of peptide solutions that remain recoverable after systemic in vivo phage selection.

molecular biology↗

bioRxiv2022

Inverse Agonist Activity of Angiotensin II Receptor Blocker Is Crucial for Prevention of Aortic Aneurysm Formation in Marfan Syndrome

BackgroundMarfan syndrome (MFS), an inherited disorder caused by FBN1 gene mutations, causes fatal aortic aneurysm. Selective angiotensin II (Ang II) type 1 (AT1) receptor blockade is a preventive option for patients with MFS aortopathy, and recent clinical studies demonstrated that the inhibitory effect of an AT1 receptor blocker (ARB) losartan on aortic aneurysm growth is equivalent to that of {beta}-blockers. At present, several ARBs are clinically available, and they have drug-specific differences in pharmacological properties. Especially, inverse agonism of ARBs has potential benefits for cardiovascular protection, but its impact on MFS aortopathy remains poorly understood. MethodsCandesartan-7H is a candesartan derivative which lacks the carboxyl group critical for inverse agonist activity and works as a neutral antagonist for AT1 receptor. Candesartan cilexetil (1 mg/kg/day), candesartan-7H (1 mg/kg/day or 20 mg/kg/day), or vehicle was administered to Fbn1C1041G/+ mice, and aortic aneurysm formation was analyzed using echocardiography, histological staining, and in situ MMP assay. Activation of TGF-{beta} signaling and mechanosensitive signaling was studied using western blot and immunohistochemical analysis. ResultsCandesartan cilexetil (1 mg/kg/day) and candesartan-7H (20 mg/kg/day) lowered blood pressures equally in Fbn1C1041G/+ mice, but that candesartan-7H (1 mg/kg/day) did not. Aortic aneurysmal progression in association with aortic wall thickening, degeneration of elastic fibers, deposition of collagen, MMP activation, and TGF-{beta} signaling activation in Fbn1C1041G/+ mice was significantly suppressed by treatment with candesartan cilexetil (1 mg/kg/day), but not by candesartan-7H even at 20 mg/kg/day. In addition, candesartan cilexetil, but not candesartan-7H, inhibited up-regulation of mechanical stress-responsive transcriptional factor Egr-1 in ascending aorta of Fbn1C1041G/+ mice. ConclusionsOur findings support a crucial role of inverse agonist activity of ARB for prevention of mechanical stress-induced AT1 receptor activation and aortic aneurysm formation in MFS mice.

pharmacology and toxicology↗

bioRxiv2022

Aberrant mechanosensitive signaling underlies activation of vascular endothelial xanthine oxidoreductase that promotes aortic aneurysm formation in Marfan syndrome

Marfan syndrome (MFS) is an inherited connective tissue disorder caused by mutations in the FBN1 gene encoding fibrillin-1, a matrix component of extracellular microfibrils. The main cause of morbidity and mortality in MFS is thoracic aortic aneurysm and dissection, but the underlying mechanisms remain undetermined. We found a significant increase in reactive oxygen species (ROS) generation in ascending aorta of MFS patients and MFS mice harboring the Fbn1 mutation (C1039G), which was associated with up-regulation of xanthine oxidoreductase (XOR) protein in aortic endothelial cells (ECs). Mechanosensitive signaling involving focal adhesion kinase (FAK)-p38 mitogen-activated protein kinase (MAPK) and early growth response-1 (Egr- 1) was aberrantly activated in ascending aorta of Fbn1C1039G/+ mice, and mechanical stress on human aortic ECs up-regulated XOR expression through FAK-p38 MAPK activation and Egr-1 up-regulation. Inhibition of XOR function by ECs-specific disruption of Xdh gene or by systemic administration of XOR inhibitor febuxostat in Fbn1C1039G/+ mice suppressed ROS generation, FAK-p38 MAPK activation, and Egr-1 up-regulation, leading to attenuation of aortic aneurysm formation. These findings unveil aberrant mechanosensitive signaling in vascular ECs triggering endothelial XOR activation and ROS generation as a culprit underlying the pathogenesis of aortic aneurysm formation in MFS, and highlight a drug repositioning approach using a uric acid lowering drug febuxostat as a potential therapy for MFS.

pathology↗

bioRxiv2020

A temporally resolved transcriptome for developing Keller explants of the Xenopus laevis dorsal marginal zone

Explanted tissues from vertebrate embryos reliably develop in culture and have provided essential paradigms for understanding embryogenesis, from early embryological investigations of induction, to the extensive study of Xenopus animal caps, to the current studies of mammalian gastruloids. Cultured explants of the Xenopus dorsal marginal zone ("Keller" explants) serve as a central paradigm for studies of convergent extension cell movements, yet we know little about the global patterns of gene expression in these explants. In an effort to more thoroughly develop this important model system, we provide here a time-resolved bulk transcriptome for developing Keller explants.

developmental biology↗

bioRxiv2020

Endothelial expression of human APP leads to cerebral amyloid angiopathy in mice

The deposition of amyloid {beta} (A{beta}) in blood vessels of the brain, known as cerebral amyloid angiopathy (CAA), is observed in more than 90% of Alzheimers disease (AD) patients. The presence of such CAA pathology is not as evident, however, in most mouse models of AD, thereby making it difficult to examine the contribution of CAA to the pathogenesis of AD. Since blood levels of soluble amyloid precursor protein (sAPP) in rodents are less than 1% of those in humans, we hypothesized that endothelial APP expression would be markedly lower in rodents, thus providing a reason for the poorly expressed CAA pathology. Here we generated mice that specifically express human APP770 in endothelial cells. These mice exhibited an age-dependent robust deposition of A{beta} in brain blood vessels but not in the parenchyma. Crossing these animals with APP knock-in mice led to an expanded CAA pathology as evidenced by increased amounts of amyloid accumulated in the cortical blood vessels. These results show that both neuronal and endothelial APP contribute cooperatively to vascular A{beta} deposition, and suggest that this mouse model will be useful for studying disease mechanisms underlying CAA and for developing novel AD therapeutics.

neuroscience↗

bioRxiv2018

Frequency and synchrony of actomyosin oscillation during PCP-dependent convergent extension

Oscillatory actomyosin flows play a key role in single cell migration and in collective cell movements that shape invertebrates embryos, but the role of such oscillations in vertebrate morphogenesis remains poorly defined. Here, data from mathematical modeling and in vivo 4D imaging of actomyosin in the Xenopus gastrula suggest that oscillatory actomyosin contractions are a general feature of convergent extension by junction shrinking. We show that synchronous intracellular flows link two spatially distinct populations of actomyosin within individual cells, but that oscillations are asynchronous between neighboring cells that share a shrinking cell-cell junction. We also show that the core PCP protein Prickle2 displays a parallel oscillatory behavior and is required for tuning the frequency of actomyosin contractions, indicating that PCP signaling controls not only the orientation of actomyosin contractions, but also their frequency. Together, these data provide new insights into the function and control of oscillatory actomyosin contractions in collective cell movement.

developmental biology↗