Selective vulnerability of cerebral vasculature to NOTCH3 variants in small vessel disease and rescue by phosphodiesterase-5 inhibitor

NOTCH3 variants cause CADASIL, the most common genetic form of small vessel disease (SVD) and vascular dementia (VaD), and increase the stroke and SVD/VaD risk. CADASIL is a systemic vasculopathy but predominantly manifests in the brain. The molecular mechanisms of CADASIL remain largely unclear with no specific available treatments. NOTCH3 is primarily expressed in vascular smooth muscle cells (VSMCs). Using human induced pluripotent stem cell (iPSC) models and developmental lineage-specific VSMC differentiation, we revealed a selective vulnerability of cerebral but not peripheral VSMC mimics to NOTCH3 variants. Transcriptomic, protein and functional analyses demonstrated a switching of CADASIL iPSC-VSMCs from a contractile to a synthetic phenotype, accompanied with extensive extracellular matrix accumulation and impairment of cell adhesion leading to anoikis. Importantly, we describe an endothelial independent nitric oxide signalling in VSMCs which was dysregulated in the CADASIL iPSC..., We resize the input image to 512×512 pixels. Then, the standard Canny edge detection algorithm is employed to outline the edges of stress fibers. Technically speaking, a Gaussian filter is applied to smooth the image whilst reducing noise. Afterwards, image gradients are computed so that potential edges can be identified. , # Data from: Selective vulnerability of cerebral vasculature to NOTCH3 variants in small vessel disease and rescue by phosphodiesterase-5 inhibitor Dataset DOI: [10.5061/dryad.2280gb66p](https://doi.org/10.5061/dryad.2280gb66p) ## Description of the data and file structure This Code is for the paper titled 'Selective vulnerability of cerebral vasculature to NOTCH3 variants in small vessel disease and rescue by phosphodiesterase-5 inhibitor'. It is permanently open and free to read/download for the entire research community (no access code is needed). 1.'`C224Y.zip`':The data contains the stress fiber samples used in this article, including one folder labeled 'C224Y'. The results of stress fiber identification for each image, including image edges and cell nuclei, are stored in the 'image' folder, while the rest of the data contains various parameters such as detected coordinates and spatial dispersion. C224Y: The images in this folder were captured to examine the distribution of t..., ,NOTCH3变异体可引发伴皮质下梗死和白质脑病的常染色体显性遗传性脑动脉病（CADASIL）——这是最常见的遗传性小血管病（small vessel disease, SVD）与血管性痴呆（vascular dementia, VaD）类型，同时会升高卒中及SVD/VaD的发病风险。CADASIL属于系统性血管病，但主要临床表现累及脑部。目前CADASIL的分子机制尚未完全阐明，且尚无特异性治疗手段。NOTCH3主要在血管平滑肌细胞（vascular smooth muscle cells, VSMCs）中表达。本研究借助人类诱导多能干细胞（human induced pluripotent stem cell, iPSC）模型及发育谱系特异性VSMC分化体系，发现脑血管而非外周血管的VSMC模拟物对NOTCH3变异体存在选择性易感性。转录组学、蛋白质组学及功能分析结果显示，CADASIL患者来源的iPSC-VSMCs从收缩表型向合成表型转换，伴随大量细胞外基质（extracellular matrix）积累、细胞黏附受损并引发失巢凋亡（anoikis）。重要的是，我们首次报道了VSMC中不依赖内皮细胞的一氧化氮信号通路（nitric oxide signalling），该通路在CADASIL的iPSC模型中出现失调。我们将输入图像统一调整至512×512像素。随后采用标准Canny边缘检测算法（Canny edge detection algorithm）勾勒应力纤维（stress fiber）的边缘。具体技术流程为：先通过高斯滤波器（Gaussian filter）平滑图像以降低噪声，之后计算图像梯度以识别潜在边缘。 # 数据来源：《小血管病中脑血管系统对NOTCH3变异体的选择性易感性及磷酸二酯酶5抑制剂（phosphodiesterase-5 inhibitor）的挽救作用》 数据集DOI：[10.5061/dryad.2280gb66p](https://doi.org/10.5061/dryad.2280gb66p) ## 数据与文件结构说明 本代码对应论文《小血管病中脑血管系统对NOTCH3变异体的选择性易感性及磷酸二酯酶5抑制剂的挽救作用》。本资源永久开放，所有科研社群均可免费读取/下载（无需访问权限码）。 1. `C224Y.zip`：本数据包包含本文所用的应力纤维样本，内含一个名为“C224Y”的文件夹。每张图像的应力纤维识别结果（包括图像边缘与细胞核信息）存储于“image”子文件夹中，其余数据则包含各类参数，如检测到的坐标值与空间离散度。 C224Y： 本文件夹内的图像用于检测t..., ,