Supplement: Sex Differences in Angiotensin-induced Vascular Diseases

  • Cassis, Lisa (PI)
  • Lin, Ai Ling (Former CoI)
  • Thatcher, Sean (Former CoI)

Grants and Contracts Details


This is a revised administrative supplement application for Research on Alzheimers Disease (AD) to NIH HLBI. The working hypothesis of the parent grant (HL107325-06) is that an interplay between sex hormones and chromosomes promotes the incidence and severity of abdominal aortic aneurysms (AAAs). Studies suggest that females are 2/3rds of the AD population, and that females with AD survive longer with the disease. The majority of studies that have attempted to address these intriguing and profound sex differences in AD have focused on sex hormones. However, up to 5% of the human genome is on the X chromosome, and GWAS studies focused on AD have not included sex chromosomes in defining mechanisms of the disease. We are using novel mouse models that enable dissection of the relative contribution of sex hormones versus sex chromosomes to sex differences in AAAs. The model uses infusion of angiotensin II (AngII) to low density lipoprotein receptor (Ldlr-/-) deficient mice fed a Western diet. As such, mice are hypertensive, hypercholesterolemic and have vascular diseases (atherosclerosis, AAAs). Preliminary data demonstrate sex differences in cerebral blood flow (CBF), with higher CBF in male than female mice. Infusion of AngII decreased CBF in both sexes, but this effect was abolished in females having only one X chromosome. These results demonstrate sex differences in CBF, a parameter linked to the early stages of dementia and impaired cognition. Moreover, sex differences in CBF may arise from sex hormone and/or sex chromosome influences. Finally, infusion of AngII as the model under study within the parent application influences CBF, supporting a role for hypertension as a risk factor for AD development. We will incorporate brain measures into our approach to define the relative role of sex hormones, as well as sex chromosomes, on hallmark parameters for AD development. This includes adding measurements of CBF, brain biochemistry, structure and function (cognition) to ongoing studies in mice with varying sex chromosome complement and in the absence or presence of sex hormones. These studies will not only provide information on the role of sex chromosomes to measures of brain function related to AD, but the role of several risk factors for AD development on brain function.
Effective start/end date3/21/125/31/22


  • National Heart Lung and Blood Institute


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