Brain vascular calcification is a prevalent age-related condition often accompanying neurodegenerative and neuroinflammatory diseases. The pathogenesis of large-vessel calcifications in peripheral tissue is well studied, but microvascular calcification in the brain remains poorly understood. Here, we report that elevated platelet-derived growth factor BB (PDGF-BB) from bone preosteoclasts contributed to cerebrovascular calcification in male mice. Aged male mice had higher serum PDGF-BB levels and a higher incidence of brain calcification compared with young mice, mainly in the thalamus. Transgenic mice with preosteoclast-specific Pdgfb overexpression exhibited elevated serum PDGF-BB levels and recapitulated age-associated thalamic calcification. Conversely, mice with preosteoclast-specific Pdgfb deletion displayed diminished age-associated thalamic calcification. In an ex vivo cerebral microvascular culture system, PDGF-BB dose-dependently promoted vascular calcification. Analysis of osteogenic gene array and single-cell RNA-Seq (scRNA-Seq) revealed that PDGF-BB upregulated multiple osteogenic differentiation genes and the phosphate transporter Slc20a1 in cerebral microvessels. Mechanistically, PDGF-BB stimulated the phosphorylation of its receptor PDGFRβ (p-PDGFRβ) and ERK (p-ERK), leading to the activation of RUNX2. This activation, in turn, induced the transcription of osteoblast differentiation genes in PCs and upregulated Slc20a1 in astrocytes. Thus, bone-derived PDGF-BB induced brain vascular calcification by activating the p-PDGFRβ/p-ERK/RUNX2 signaling cascade in cerebrovascular cells.

中文翻译：

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骨源性 PDGF-BB 促进雄性小鼠脑血管钙化

脑血管钙化是一种普遍存在的与年龄相关的疾病，通常伴随神经退行性和神经炎症性疾病。外周组织大血管钙化的发病机制已得到充分研究，但大脑微血管钙化仍知之甚少。在此，我们报告称，骨前破骨细胞中血小板衍生生长因子 BB (PDGF-BB) 的升高导致雄性小鼠的脑血管钙化。与年轻小鼠相比，老年雄性小鼠血清PDGF-BB水平较高，脑钙化发生率较高，主要发生在丘脑。具有前破骨细胞特异性Pdgfb过表达的转基因小鼠表现出血清 PDGF-BB 水平升高和再现与年龄相关的丘脑钙化。相反，具有前破骨细胞特异性Pdgfb缺失的小鼠表现出与年龄相关的丘脑钙化减少。在离体脑微血管培养系统中，PDGF-BB剂量依赖性地促进血管钙化。成骨基因阵列和单细胞RNA-Seq（scRNA-Seq）分析表明，PDGF-BB上调脑微血管中的多个成骨分化基因和磷酸盐转运蛋白Slc20a1 。从机制上讲，PDGF-BB刺激其受体PDGFRβ（p-PDGFRβ）和ERK（p-ERK）的磷酸化，导致RUNX2的激活。这种激活反过来又诱导 PC 中成骨细胞分化基因的转录，并上调星形胶质细胞中的Slc20a1。因此，骨源性PDGF-BB通过激活脑血管细胞中的p-PDGFRβ/p-ERK/RUNX2信号级联来诱导脑血管钙化。