Fellowship for S Khan--Role of Exosomes in Senescent Signaling and Aging-Related Vascular Dysfunction

It is now established that cell-to cell communications play an important role in the regulation of various medical conditions including cardiovascular diseases. Over the last few years, a considerable amount of experimental evidence suggested that cells can exchange information through the release of specialized membranous nano-sized vesicles termed exosomes. Exosomes contain proteins, mRNA, miRNAs, and signaling molecules that are believed to play a pivotal role in intracellular communication. Recent in vitro data indicate that exosomemediated cell-to-cell communications have been implicated in the spread of several age-related neurodegenerative diseases and cancer. In addition, plasminogen activator inhibitor-1 (PAI-1) plays a crucial role in the development of CVD and is also essential for cell-to-cell communication. PAI-1 is elevated in a variety of clinical situations that are associated with increased risk of CVD. Recent insights into the biology of PAI-1 suggest that it may contribute to the development of cardiovascular disease. In a murine model of hypertension, both genetic PAI-1 deficiency and pharmacological inhibition of PAI-1 protected against the development of hypertension and subsequent structural vascular changes and hypertension. In this proposal we will explore the hypothesis that signals generated during HTN on the cellular level can be transmitted by exosomes. We anticipate that the studies proposed here will not only establish the paradigm of exosomes as regulators of HTN, but will also broadly advance our understanding of how signals are transmitted in the setting of CVD.