Nasim Sana, Bichsel Colette, Pinto Anna, Alexandrescu Sanda, Kozakewich Harry, Bischoff Joyce
Vascular Biology Program, Boston Children's Hospital and Harvard Medical School, Boston, MA, 02115, USA.
Department of Surgery, Boston Children's Hospital and Harvard Medical School, Boston, MA, 02115, USA.
bioRxiv. 2024 Jun 19:2024.06.19.599711. doi: 10.1101/2024.06.19.599711.
Capillary malformations (CM) are congenital vascular irregularities of capillary and venous blood vessels that appear in the skin, leptomeninges of the brain, and the choroid of the eye in the disorder known as Sturge Weber Syndrome (SWS). More common are non-syndromic CM found only in the skin, without brain or ocular involvement. A somatic activating mutation in (p.R183Q) is found in ~90% of syndromic and non-syndromic CM specimens and is present in CD31 endothelial cells isolated from brain and skin CM specimens. Endothelial expression of the p.R183Q variant is sufficient to form CM-like vessels in mice. Given the distinct features and functions of blood vessels in the brain versus the skin, we examined the features of CM vessels in both tissues to gain insights into the pathogenesis of CM. Herein, we present morphologic characteristics of CM observed in specimen from brain and skin. The p.R183Q variant allelic frequency in each specimen was determined by droplet digital PCR. Sections were stained for endothelial cells, tight junctions, mural cells, and macrophages to assess the endothelium as well as perivascular constituents. CM blood vessels in brain and skin were enlarged, exhibited fibrin leakage and reduced zona occludin-1, and were surrounded by MRC1/LYVE1 macrophages. In contrast, the CMs from brain and skin differ in endothelial sprouting activity and localization of mural cells. These characteristics might be helpful in the development of targeted and/or tissue specific therapies to prevent or reverse non-syndromic and syndromic CM.
毛细血管畸形（CM）是一种先天性血管异常，涉及毛细血管和静脉血管，出现在被称为斯特奇-韦伯综合征（SWS）的疾病中的皮肤、脑软脑膜和眼脉络膜中。更常见的是仅发生在皮肤的非综合征性CM，不涉及脑或眼。约90%的综合征性和非综合征性CM标本中发现了（p.R183Q）的体细胞激活突变，并且存在于从脑和皮肤CM标本中分离出的CD31内皮细胞中。p.R183Q变体在内皮细胞中的表达足以在小鼠中形成类似CM的血管。鉴于脑和皮肤中血管的不同特征和功能，我们研究了这两种组织中CM血管的特征，以深入了解CM的发病机制。在此，我们展示了在脑和皮肤标本中观察到的CM的形态学特征。通过液滴数字PCR测定每个标本中p.R183Q变体的等位基因频率。切片用内皮细胞、紧密连接、壁细胞和巨噬细胞染色，以评估内皮以及血管周围成分。脑和皮肤中的CM血管扩张，出现纤维蛋白渗漏且闭合蛋白-1减少，并被MRC1/LYVE1巨噬细胞包围。相比之下，脑和皮肤中的CM在内皮芽生活性和壁细胞定位方面存在差异。这些特征可能有助于开发针对性和/或组织特异性疗法，以预防或逆转非综合征性和综合征性CM。
