Critical Roles of Endothelial FOXO-1 Activation in Endothelial Dysfunction during Hypertension Development

Hypertension is a chronic vascular disease and its prevalence continues to increase, particularly in developing countries, causing heavy healthcare burden. Hypertension is among the top risk factors for the development and progression of cardiovascular diseases such as stroke and heart failure which remain the major cause of morbidity and mortality globally. It is still in urgent need to explore new mechanisms underlying vascular dysfunction associated with hypertension and to identify novel therapeutic targets and strategies for the prevention and treatment of hypertension and its complications.Healthy function of endothelial cells lining the lumen of blood vessels plays an essential role in vascular homeostasis and blood pressure regulation through balancing the impacts of both endothelium-derived relaxing factors, such as nitric oxide (NO) and endothelium-derived contracting factors, such as reactive oxygen species (ROS) on vascular resistance to blood flow in tissues andorgans. Disruption of this fine-tuned balance in hypertension, obesity and diabetes is usually caused by decreased activity of NO-generating enzyme, endothelial NO synthase (eNOS) or/and increased production of ROS-dependent cyclooxygenase 2 (COX2)-derived vasoconstrictive prostaglandins, which is commonly referred to endothelial dysfunction, the critical trigger for the initiation ofcardiovascular pathogenesis. FOXO1, a transcription factor, is one of essential players in controlling cell proliferation, differentiation and metabolism. FOXO1 deficiency leads to reduced formation of new blood vessels. However, it is still unknown whether endothelial FOXO1 participates in the induction and maintenance of endothelial dysfunction under hypertensive conditions. Our preliminary results show an increasedexpression of endothelial FOXO1 in arteries from patients with hypertension and from angiotensin IIinducedhypertensive mice. The RNA sequencing data show that hypertension and its complications are top-enriched in FOXO1-overexpressing human endothelial cells. We have recently generated endothelium-specific Foxo-1 knockout mice and found that FOXO1 inhibition in endothelial cells partially reverses angiotensin II (one of critical mediators for hypertension development)-inducedblood pressure elevation and endothelial dysfunction in mice. FOXO1 overexpression inhibits eNOS expression and raises ROS production and COX2 expression in human endothelial cells. On the other hand, FOXO1 silencing and FOXO1 inhibitor reduce COX2 expression, and FOXO1 inhibitor suppresses angiotensin II-induced COX2-mediated endothelium-dependent contractions. Besides, the binding site of FOXO1 in the NOS3 (encoding eNOS) and PTGS2 (encoding COX2) promoter is predicted by JASPAR2022 database. These initial exciting results suggest that FOXO1 activation impairs endothelial function in hypertension through suppression of eNOS and activation of COX2 in endothelial cells. Detailed studies are required to support inhibition of endothelial FOXO1 as another effective therapeutic strategy for the treatment of vascular disorder in hypertension.This proposed study shall be the first of its type to investigate the critical roles of endothelial FOXO1 in endothelial dysfunction during hypertension development and to identify and develop drugs targeting FOXO1 for the treatment of hypertension. Specifically, we will investigate (1) the role of endothelial FOXO1 in angiotensin II-induced hypertension; (2) the mechanisms underlying thebeneficial effect of endothelial FOXO1 inhibition against hypertension; and (3) establish a FOXO1 inhibitor screening platform for anti-hypertensive drug discovery