Role of Notch3/RBP-JK on renal, cardiac and brain function under basal conditions and during hypertension – HyperNotch3

Control of local, peripheral hemodynamics has major clinical implications in a variety of conditions and diseases in which myogenic tone and autoregulation are key components, such as hypertension, stroke, chronic kidney disease, heart failure, vascular dementia and atherosclerosis.

The general objective of this proposal is to get insights into the role of Notch3 in the functional and structural adaptation of kidney, brain and heart in response to acute and chronic increase of arterial blood pressure, using novel conditional genetic models of mice.

The specific hypothesis behind this proposal, which is strongly supported by our preliminary studies, is that Notch3 is involved in the maintenance and plasticity of adult resistance arteries under normal conditions and participates in the adaptation of these vessels to chronic alteration of the blood pressure. Since the structural and functional alterations of the resistance vessels are an important part of the pathogenesis of the deleterious effects of hypertension on the brain, kidney and heart, we further hypothesize that Notch3 signaling contributes to the deleterious effects of hypertension on these tissues.

Specific aims are to:
1) Investigate the function of Notch3/RBP-JK in the adult vasculature under basal conditions
2) Investigate the function of Notch3/RBP-JK in the adult vasculature under short term induced hypertension
3) Investigate the contribution of Notch3/RBP-JK to the deleterious effects of chronic hypertension on the brain, kidney and heart

To achieve these goals, we will use two conditional gain- and loss- of function alleles of Notch3/RBP-Jk in vascular smooth muscle cells in the mouse. These two strains of mice have been recently developed by partner 2, are viable and ready for immediate use. Our plan is to combine state of the art genetic, molecular, biochemical, histological as well as ex vivo and in vivo functional approaches.

Originality-Novelty: This application builds upon the complementary expertise of the 3 teams. The laboratory of Christos Chatziantoniou has a recognized expertise in renal physiopathology. Anne Joutel’s team has an important experience with the study of Notch3 with particular focus on the cerebral vasculature. Jane-Lise Samuel’s laboratory is a well known expert on cardiovascular physiopathology. The implementation of the experimental objectives of the project relies on the use of cutting edge interdisciplinary technology, such as the development of two conditional transgenic strains, the live recording of local hemodynamics in mice and methods of molecular and cellular biology to reveal the mechanisms involved. Notch3 was classically considered as an important gene for the development of vessels in early life, with limited implication in the vessel function during adulthood. The recently results from the partners teams strongly suggest that Notch3/RBP-JK signaling can be an important regulator of vascular function in adult animals. This research proposal aims to create novel knowledge using the original approach of conditional induction of loss or gain of Notch3/RBP-JK signaling. This project will produce novel information firstly on the basic regulatory mechanisms, and secondly on the mechanisms involved in the development of a major pathology.

Relevance-Importance: Demonstration of a local involvement of Notch-3 activity and/or signaling in the progression of nephrosclerosis, brain damage and/or heart disease will open a completely new field in our understanding of the physiopathological mechanisms affecting the function of these key organs during changes of arterial pressure. Thus, research applications will be wide, ranging from cellular biology to characterize the consequences of Notch3 pathway impairment or activation to clinical studies looking for new markers of progression of renal, brain and heart disease and to discovering novel targets for therapy of these diseases.