The role of IGF-1 signaling in vascular smooth muscle cells in age-related vascular cognitive impairment and dementia

项目概要/摘要 与年龄相关的血管性认知障碍和痴呆（VCID），阿尔茨海默氏病的一个亚组及相关疾病 痴呆症（ADRD）是老年人残疾和生活质量下降的常见原因。近期广泛 数据表明，大脑中的微血管病变在这些过程中发挥着核心作用。这样的一位 病理学是脑微出血（CMH），是脑内小血管破裂的结果 并逐渐损害神经元功能。 CMH 的发病率随着年龄和高血压的增加而急剧增加 是与年龄相关的认知能力下降的主要原因之一。然而 CMH 和 CMH 的潜在细胞机制 血管脆性增加的情况尚不清楚，因此尚无减轻 CMH 的治疗干预措施。血 血管完整性需要血管平滑肌细胞 (VSMC) 的可塑性，该细胞表现出从 为了应对压力而高度收缩，形成保护性、抗脆弱性表型。衰老从根本上改变VSMC 表型转换，抑制这些保护性 VSMC 功能的采用，否则这些功能会得到促进 胰岛素样生长因子（IGF）-1。循环中的 IGF-1 水平随着年龄的增长而急剧下降。 IGF-1 水平低 在我们的啮齿动物模型中增加脑微血管疾病的风险并促进 CMH 的发展， 支持 IGF-1 缺乏在与年龄相关的血管脆性中的作用。我们的假设是 VSMC 受损 IGF-1 缺乏导致的可塑性和功能在脑血管脆性增加和 随着年龄的增长，CMH 的发展和认知能力下降。目标 1 将检验 VSMC 有助于 IGF-1 信号传导缺陷模型中 VCID/ADRD 表型的发展。我们将使用新型 VSMC 特异性 IGF- 1 受体敲除系探讨 VSMC 在 CMH 发展、肌源性自动调节受损中的作用 应对高血压以及随之而来的认知能力下降。目标 2 将确定 具有适应不良表型的 VSMC 和具有诱导的保护表型的 VSMC 之间的动态平衡 与年龄相关的 IGF1 减少。为此，我们将解决 VSMC 在体内的可塑性问题， 评估 Igf1r 缺陷 CMH 脑血管中的保护性和适应不良 VSMC 表型 模型。目标 3 将评估控制适应不良和保护性 VSMC 的转录机制 血管脆性/CMH 区域和周围完整血管的表型。谱系追踪基因小鼠 衰老和 IGF-1 缺乏模型，结合单细胞 RNA 测序，将用于评估 新型转录调节因子在采用不同 VSMC 表型中的作用。亲脆弱性和反脆弱性 VSMC 表型状态将与 CMH 的位置在空间上重叠，以检验 CMH 发生的假设 主要发生在 VSMC 显示适应不良表型的区域。这些科学技术创新 研究将显着增强我们对 IGF-1 缺乏在 CMH 发展中作用的理解 并将提供对潜在细胞机制的深入了解，这对于开发有效的细胞机制至关重要 疗法。

PROJECT SUMMARY/ABSTRACT Age-related vascular cognitive impairment and dementia (VCID), a subgroup of Alzheimer’s Disease and Related Dementias (ADRD) is a common cause of disability and reduced quality of life among the elderly. Extensive recent data have demonstrated that microvascular pathologies in the brain play a central role in these processes. One such pathology is cerebral microhemorrhages (CMH) which are the result of rupture of small intracerebral blood vessels and progressively impairs neuronal function. The incidence of CMH dramatically increases with age and hypertension is one of the major causes for age-related cognitive decline. Yet the underlying cellular mechanisms for CMH and increased vascular fragility are unknown, and thus therapeutic interventions to mitigate CMH are not available. Blood vessel integrity requires plasticity of vascular smooth muscle cells (VSMCs), which exhibit an adaptive switch from a highly contractile to a protective, anti-fragility phenotype in response to stress. Aging fundamentally alters VSMC phenotypic switching, suppressing the adoption of these protective VSMC features, which are otherwise promoted by insulin-like growth factor (IGF)-1. Circulating IGF-1 levels are dramatically decreased with age. Low IGF-1 levels increase the risk for cerebromicrovascular disease and promote the development of CMH in our rodent models, supporting a role for IGF-1 deficiency in age-related vascular fragility. Our hypothesis is that impaired VSMC plasticity and function due to IGF-1 deficiency has a fundamental role in increased cerebrovascular fragility and development of CMH and cognitive decline with age. Aim 1 will test the hypothesis that VSMCs contribute to the development of VCID/ADRD phenotypes in IGF-1 signaling-deficient models. We will use novel VSMC-specific IGF- 1 receptor knockout lines to probe the role of VSMCs in the development of CMH, impaired myogenic autoregulation in response to hypertension, and the consequent development of cognitive decline. Aim 2 will determine the dynamic balance between VSMCs with maladaptive phenotypes and VSMCs with protective phenotypes induced by age-dependent decrease of IGF1. In this aim we will address the question of VSMC plasticity in vivo, evaluating both protective and maladaptive VSMC phenotypes in the cerebrovasculature of Igf1r-deficient CMH models. Aim 3 will evaluate the transcriptional mechanisms governing maladaptive and protective VSMC phenotypes in regions of vascular fragility/CMH and in surrounding intact vessels. Lineage tracing genetic mouse models of aging and IGF-1 deficiency, coupled with single-cell RNA-sequencing, will be used to evaluate the role of novel transcriptional regulators in the adoption of diverse VSMC phenotypes. Pro- and anti-fragility VSMC phenotypic states will be spatially overlaid with the location of CMH to test the hypothesis that CMH occur primarily in regions where VSMCs show a maladaptive phenotype. These scientifically and technically innovative studies will significantly enhance our understanding of the role of IGF-1 deficiency in the development of CMH and will provide insight into underlying cellular mechanisms which are critical for the development of effective therapies.