Defining a new mechanism of blood pressure regulation and its role during sepsis

Dysregulation in blood pressure is a leading cause of mortality as it is causatively associated with cardiovascular disease and the pathology that underlies sepsis. Therefore, it is important that we improve our understanding of how blood pressure is regulated, so that patients can be provided with effective therapy. In this study we aim to explore a newly identified mechanism that is likely to explain how infection can lead to changes in blood pressure. This is through the activation of a cellular DNA sensor named cGAS. Once activated by DNA derived from bacteria or viruses this protein generates a small molecule called cGAMP, which we have discovered can mediate vessel relaxation and lowering of blood pressure through a novel process. The aim of this study is to further investigate this new process and its role in regulating blood pressure, as well as in the underlying pathology of sepsis. Here it anticipated that findings with provide greater insight into how blood pressure is regulated, as well as new targets for therapy.

We have recently identified an important new mechanism by which the innate immune system is likely to regulate blood pressure. This process is mediated by activation of the DNA sensor cGAS within the endothelium, which generates cGAMP that is then transported into vascular smooth muscle cells where it can directly activate PKG1. This novel mechanism of PKG1 activation is likely to play an important role in the regulation of blood pressure during infection and contribute to the pathology that underlies sepsis. Here the aim is to further characterise this new mode of PKG1 activation by using an integrative approach to assess the underlying biological processes involved from the molecular level to intact tissue. In addition, we aim to further investigate the biological importance of this new mechanism by assessing blood pressure in healthy and septic wild-type, STING knockout and LRCC8a smooth muscle-specific knockout mice. It is anticipated findings will provide a novel mechanism of crosstalk between the innate immune system and blood pressure regulation, as well as new targets for therapy.