Role of PDGFRa and vascular progenitor cells in vascular remodeling during arterial hypertension – VAPROREM

Part 1: To characterize the role of this pathway in hypertension, we used mouse models that activate this receptor. We have characterized the alterations induced at arterial pressure and vascular level: artery wall composition, vascular cell proliferation, changes in the production of vasoactive factors, measurement of arterial mechanical and contractile properties of resistance and conductance. We investigated whether this pathway is involved in vascular remodeling in a mouse model of hypertension.

Part 2: We studied the role of cells expressing this receptor in vivo, using models that allow tracking of these cells after receptor activation.

Part 3: Activation of this receptor does not induce hypertension in female mice, and we have studied the role of different hormones in mice to understand the mechanisms involved in this protection by inhibiting their production.

Part 1:

We characterized the mice after induction of receptor activation. Male mice develop arterial hypertension as early as 2 months for 50% of them, without any major cardiac alterations. Activation of the receptor does not alter vascular reactivity, but does lead to an increase in the wall thickness of small arteries such as the mesenteric arteries, with an increase in the number of VSMCs (hypertrophic remodeling), which could contribute to the increase in pressure. Early on, we observed a proliferation of cells expressing this receptor around the vessels and an absence of proliferation of VSMCs, suggesting that these cells multiplying around the vessels are the source of new VSMCs.

We studied the hypervolemic hypertension model (by renal water reabsorption). However, in this model, we saw no activation of the pathway studied in the walls of patient arteries. We are studying other models of hypertension to determine the role of this pathway.

Part 2:

We observed an increase in the number of VSMCs derived from cells expressing the receptor (fluorescently labeled). However, the model is difficult to follow because the labeling is complicated to measure in small vessels. This is the last measurement required before submission of the article.

Part 3: Female mice do not develop hypertension after activation of this receptor. They seem to adapt the relaxation of their small arteries. We are in the process of identifying the pathways involved in this adaptation.

Hormone treatment experiments in the receptor activation model are underway, and suggest a role for some of them in modifying endothelial function in response to activation of the pathway studied.

This project has yielded major results in understanding the regulation of resistance artery structure and has opened up several avenues for further research:

1/ Finalization of the 2 articles on the role of the receptor in hypertension in males and on the male-female difference

2/ Setting up of new projects on the identification of players in arterial remodeling and hypertension. This has prompted me to develop a clinical collaboration to study the small arteries of hypertensive patients. This project could provide new insights into the actors modulated in these arteries.

3/ Development of new hypertension models to verify the role of the receptor in this context.

Arterial hypertension is a multifactorial heterogeneous disease, which constitutes a major risk factor for cardiovascular diseases. More than 870 Million persons develop hypertension worldwide and around 15% of these patients are resistant to current therapies. Thus, we need to discover new mechanisms to widen treatments options. Vascular wall stress adaptation to mechanical load leads to structural modifications of large and small arteries involving endothelial cells dysfunction, hypertrophy and proliferation of vascular smooth muscle cells (VSMC) and extracellular matrix rearrangement. These alterations are induced by high blood pressure but also participate in the maintenance of hypertension. Our preliminary results suggest that a growth factor receptor could be a new player in the control of vascular structure and blood pressure. Constitutive activation of this receptor induces hypertension and vascular remodeling, thus providing a new hypertension model. In addition, our data suggest that progenitor cells could produce new VSMC after activation of this receptor participating in the vascular remodeling observed in this model. Our working hypothesis is that activation of this pathway recruits vascular progenitor cells to produce new VSMC leading to vascular remodeling and to hypertension.
Our project is to demonstrate the role of this pathway and to identify the cells that are regulated by this receptor.
Task 1: We will characterize the role of this pathway in hypertension. We will use several mouse models to activate and inactivate this pathway and characterize the alterations in blood pressure, vascular structure, vascular reactivity. This will be studied by following blood pressure changes and by studying vascular structure alterations: identifying extracellular matrix composition alteration, measuring vascular cell proliferation and apoptosis, measuring vessel regulating factors, studying conductance and resistance vessels mechanical properties and contractility. Using blocker or knock-out mice, we will determine if this pathway is involved in the development of high blood pressure and vascular remodeling in 2 well established hypertension models: Angiotensin II infusion and DOCA-salt hypertension models.
Task 2: We will study the cells that respond to this growth factor using in vitro culture and cell lineage tracing mouse models. The role of these cells will also be evaluated in the 2 other hypertension models.
Task 3: Regulation of this pathway leads to the development of hypertension only in male mice and we will study the role of estrogen and testosterone to understand the mechanisms involved in the protection of female mice. Using castrated male and female mice receiving sex hormones or not, we will follow the blood pressure level at different time points after activating this receptor. Vascular structure and reactivity will also be studied in these mice to determine whether protection against blood pressure increase is associated with protection against to vascular alterations.
The origin and the regulation of vascular remodeling is a major issue in the field of research on vascular diseases. Our project is to address new hypotheses on the role of vascular progenitor cells in hypertensive vascular remodeling and on the role of a new pathway which could also participate in the sexual dimorphism in the disease development. This project will contribute to the understanding of the underlying cellular heterogeneity and hierarchical relationships between vessel wall cells. We expect to bring out new pathways and new players involved in vascular remodeling and adaptation to changes in mechanical strain.