Periodic Reporting for period 1 - MERC (Molecular mechanisms regulating cardiovascular remodeling by Adamts1)
Reporting period: 2016-06-01 to 2018-05-31
Ascending aorta dilation is a frequent cardiovascular complication of aortic valvular diseases, atherosclerosis, systemic arterial hypertension and genetic disorders. Ascending aorta aneurysms leading to dissections or rupture are major diseases affecting the aorta and are a common cause of premature deaths, such as Marfan syndrome or familial forms of non-syndromic thoracic aortic aneurysm and dissection. No clear explanation for the underlying molecular mechanisms has been found yet, nor is there an effective pharmacological treatment of these diseases. It is of paramount importance that our knowledge of the mediators of the diseases can be improved, so that pharmacological strategies can be designed in order to improve the quality and lifespan of the patients suffering these diseases.
The MERC project seeks to clarify the molecular mechanisms that lead to ascending aorta aneurysms in the conditions mentioned. Previous work by the laboratory established >150 genes highly regulated by angiotensin II in vascular cells. One of such genes, Adamts1, was found to be a major mediator in vascular wall remodeling. Similar to mouse models of Marfan's disease, Adamts1+/- and Adamts1-/- mice present aortic dilation, aneurysms and medial degeneration. Specifically, NOS2 was found to be induced by Adamts1 deficiency.
Based on those results, this project proposed to study the molecular mechanisms mediating these aortic diseases in mice, potentially providing a model for the study of the mechanisms in humans. Thus, the first aim of the project was to better characterize the roles of the isoforms of NOS in Adamts1-defficient mice and the signaling pathways downstream NOS2. A second aim was to determine potential common mechanisms of the aortopathies in Adamts1-defficient mice and Marfan mice, as well as in Marfan patients
The MERC project seeks to clarify the molecular mechanisms that lead to ascending aorta aneurysms in the conditions mentioned. Previous work by the laboratory established >150 genes highly regulated by angiotensin II in vascular cells. One of such genes, Adamts1, was found to be a major mediator in vascular wall remodeling. Similar to mouse models of Marfan's disease, Adamts1+/- and Adamts1-/- mice present aortic dilation, aneurysms and medial degeneration. Specifically, NOS2 was found to be induced by Adamts1 deficiency.
Based on those results, this project proposed to study the molecular mechanisms mediating these aortic diseases in mice, potentially providing a model for the study of the mechanisms in humans. Thus, the first aim of the project was to better characterize the roles of the isoforms of NOS in Adamts1-defficient mice and the signaling pathways downstream NOS2. A second aim was to determine potential common mechanisms of the aortopathies in Adamts1-defficient mice and Marfan mice, as well as in Marfan patients
A first aim of this project was to characterize the molecular mechanisms underlying Adamts1-defficiency-mediated activation of NOS. This was fully accomplished. NOS2 was found to be the main NOS behind the rise of NO levels, and NOS2 KD protected against the aortic dilation induced by silencing of Adamts1. A role for AKT as the upstream activator of NOS2 was also demonstrated, while a role for metalloproteases downstream of NO signaling (that could account for the loss of elastic fiber integrity) was also explored.
A second aim of the project involved exploring a mouse model of Marfan’s disease (MFS mice), and this aim was partially completed before the premature end of the project. It was demonstrated that the aortic phenotype of both MFS and Adamts1-deficient mice is similar and can be counteracted by the pharmacological inhibition of NOS2. Furthermore, MFS mice showed reduced levels of Adamts1, which also occurs in aortic sections of human Marfan patients. Finally, the role of the substrates of Adamts1 was explored both in their capacity to mediate the aortic phenotype and to induce the NO signaling pathway. It was shown that versican induced a sustained AKT activation, and that silencing of Versican reverted aortic dilation and NOS2 upregulation seen in MFS mice.
A second aim of the project involved exploring a mouse model of Marfan’s disease (MFS mice), and this aim was partially completed before the premature end of the project. It was demonstrated that the aortic phenotype of both MFS and Adamts1-deficient mice is similar and can be counteracted by the pharmacological inhibition of NOS2. Furthermore, MFS mice showed reduced levels of Adamts1, which also occurs in aortic sections of human Marfan patients. Finally, the role of the substrates of Adamts1 was explored both in their capacity to mediate the aortic phenotype and to induce the NO signaling pathway. It was shown that versican induced a sustained AKT activation, and that silencing of Versican reverted aortic dilation and NOS2 upregulation seen in MFS mice.
The research line that encompasses the project has generated multiple promising results. The ultimate aim of this project is to better understand the molecular mechanisms involved in aortic diseases and thus to facilitate the development of pharmacological treatments to alleviate or prevent the progression of aneurysms. The discoveries made during this project include a paradigm shift regarding the role of NO in these disease, an advanced exploration of the potential molecular mechanisms underlying the pathologies, and an emerging model which will act as the global framework that brings together the mechanisms, phenotypes and which could be applicable to different diseases. Based on the line of research as a whole, the group is currently exploring how to translate these discoveries into concrete applications for prognosis and treatment of aneurysm development in aortic diseases. The current publication track by the group (i.e. Oller et al., Nat Medicine 2017; de Carcer et al., Nat Medicine 2017; Villahoz et al., Nat Commun 2019, among others) are the clear proof that the research by the group is going in the right direction.