Grant: Project Grant

As people age, their arteries stiffen, leading to various cardiovascular diseases. Arterial stiffening, as the primary feature of aging, involves mechanisms present both inside (active) and outside (passive) of the smooth muscle cells (SMCs) that make up the arterial walls. Currently, what regulates these mechanisms remains largely unclear. We recently developed a novel mouse model in which we deleted a gene, called Atg7, in the SMCs of 5-month old mice. Atg7 is responsible for the recycling process of cellular materials (autophagy, or "self-eating"). We found these mice had arterial stiffening, hypertension and several disease changes in arteries like those in naturally aged animals (>18 months old). These results are novel because the previous mouse models with the Atg7 gene deleted in embryos did not show these changes. Therefore, we will use this mouse model to explore how Atg7 elimination - i.e. the disruption of autophagy - impacts the active and passive mechanisms of arterial stiffening. We will also study whether these vascular changes are present in naturally aged mice. We also observed an increase in YAP (Yes-associated protein 1) in SMCs from our Atg7 mouse model. YAP is known to be involved in arterial stiffness; therefore, we will examine the role of YAP in arterial stiffening by deleting the YAP gene in SMCs in our Atg7 mouse model. In our Atg7 mouse model, we also found an increase in DNA content in the nuclei of arterial SMCs, called polyploidization. Given that SMC polyploidization is also present in naturally aged arteries, we will examine whether SMC polyploidization contributes to arterial stiffening induced by Atg7 deletion in SMCs. In sum, our proposed studies using a unique mouse model will reveal the mechanisms of arterial stiffness and associated cardiovascular diseases. Our research outcome will help develop new drugs and treatments for aging-associated cardiovascular diseases.