It is well documented that people who live in cold regions have increased prevalence of hypertension and related cardiovascular diseases. Indeed, cold temperatures increase blood pressure (BP). In the US, the highest morbidity and mortality due to cardiovascular disease occur during the cold winter season. Cold temperatures make hypertension severer and trigger myocardial infarction and stroke in hypertensive patients. Intermittent exposure to moderate cold (5C) causes hypertension in mice and rats within three weeks, namely cold-induced hypertension (CIH). Our long-term goal is to understand how cold temperatures cause hypertension and related cardiovascular diseases in order to develop preventive and therapeutic strategies. The objective of this application is to assess if upregulation of coupling factor 6 (CF6), a subunit of ATP synthase, contributes to cold-induced salt sensitivity, vascular dysfunction, and CIH. The central hypothesis is that intermittent exposure to cold upregulates CF6 which impairs Na excretion and causes vascular dysfunction contributing to CIH. The objective will be achieved by pursuing three complementary specific aims using a combination of several novel approaches including in vivo cell-specific gene delivery, endothelial cell-specific gene knockout, and real-time monitoring of blood pressure (telemetry). The specific aims are: (1) Determine if the upregulation of CF6 impairs renal Na excretion (salt sensitivity) and causes vascular dysfunction contributing to CIH. (2) Investigate the molecular mechanism that mediates the role of CF6 in cold-induced impairment in renal Na excretion. (3) Investigate the molecular mechanism that mediates the role of CF6 in cold- induced vascular dysfunction. The findings from the proposed studies will reveal novel roles of CF6 in regulating renal Na excretion and vascular function which were previously unidentified. Completion of the proposed research will put us in an outstanding position to develop preventive and therapeutic strategies for hypertension by targeting CF6. Therefore, the proposed work is innovative and significant because it utilizes state-of-the-art approaches to addresses an important medical problem associated with cold stress which affects a large population but remains poorly explored.