Interplay of Sex Hormones and Chromosomes in Vascular Oxidative Stress and Arterial Stiffening

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Project Summary Sex steroids and chromosomes both contribute to the sexual dimorphism in CVD. Vascular oxidative stress is one mechanism that is elevated in men compared with women due to the protective effects of estrogen. While the impact of sex hormones is extensively studied, sex chromosomes complementation has been overlooked in the context of CVD. Female sex chromosomes (XX) are associated with worse cardiovascular outcomes during hypertension, stroke, and pulmonary hypertension. Remarkably, studies on the role of sex chromosomes in vascular oxidative stress are still lacking. Therefore, we have proposed to elucidate the role of sex chromosomes in vascular oxidative stress associated with CVD. In the K99 phase, our first aim will establish that in the absence of sex hormones, XX promotes vascular ROS and arterial stiffening. This aim will unequivocally determine the impact of sex chromosomes on arterial stiffness and elucidate the molecular mechanisms. We will use the four core genotype (FCG) mice which includes females with ovaries and testes and males with testes and ovaries. We will also use state-of-the-art equipment such as high resolution ultrasound for pulse wave velocity, biaxial pressure myography for arterial biomechanics, and electron spin spectroscopy for assessing reactive oxygen species. The second aim will elucidate the molecular mechanisms by which estrogen preserves X chromosome inactivation to suppress X-linked gene expression and vascular oxidative stress. We will use fluorescent in situ hybridization to localize X-inactive specific transcript and map the dynamic structure and localization of the sex chromosomes. Our overall goal is to determine whether sex hormones and chromosomes interact in CVD and are associated with vascular oxidative stress. In the future, identifying X-linked genes that contribute to oxidative stress will provide novel targets for sex-specific therapies to treat or prevent CVD. In the R00 phase, the third, fourth and fifth aims will determine whether estrogen mediated Xist RNA localization impacts telomere length, mitochondrial oxidative stress and T-cell mediated vascular damage. The MOSAIC K99/R00 award will enable my training and career development in novel techniques that will allow separation from my mentor and transition to independency. Moreover, this proposal will not only progress scientific research in CVD, but advance the training and fellowship of future minority scientists in biomedical sciences