Periodic Reporting for period 1 - FIB-AGE (Untangling fibroblast plasticity in vascular ageing)
Período documentado: 2021-06-01 hasta 2023-05-31
Everyone wants to grow old, but no one wants to feel old. In fact, age is the most important risk factor for cardiovascular disease, such as a heart attack or stroke. Yet there is no effective treatment to prevent age-associated changes leading to cardiovascular disease.
The wall of a blood vessel consists of three layers. The inner two layers protect against clotting, accumulation of inflammatory cells, and help regulate blood pressure. The contribution of cells in the outer perivascular layer is still unknown. However, it is known that flexible blood vessels are essential for proper regulation of blood pressure and the proper functioning of the heart and organs. Aging is accompanied by the accumulation of connective tissue in the vessels, which leads to stiffness of the blood vessels. These stiff blood vessels are a significant cause of high blood pressure and the development of cardiovascular diseases such as heart attacks and strokes. This is particularly important now as people in our Western world are living longer but also want to experience it in good health.
Current treatments are mainly aimed at the function of the two inner layers of the vessel wall and cannot prevent all heart attacks or strokes. We proposed that connective-tissue producing cells in the outer, perivascular cell layer play a causal role in vascular ageing. Therefore, we used advanced technology and identified new gene markers for these perivascular cells.
We use modern technology to study changes in individual cells. With older technology, differences could not be observed because a large mix of whole tissues and all cell types was used. This is similar to a smoothie where the individual fruits cannot be seen anymore. This preliminary work demonstrates that there is indeed an increase in a specific group of connective tissue-producing cells during aging. This has led to the hypothesis that we will now investigate: Reprogramming the function of perivascular cells can reduce damage caused by vascular aging.
We will study perivascular cell function in vivo, in vitro and in interventional studies ex vivo, in so far unimaginable detail. By sophisticated integration of this obtained data, we aim to identify key players promoting vascular ageing and dysfunction and suggest first interventional targets for future therapy to keep our vessels healthy for longer.
The wall of a blood vessel consists of three layers. The inner two layers protect against clotting, accumulation of inflammatory cells, and help regulate blood pressure. The contribution of cells in the outer perivascular layer is still unknown. However, it is known that flexible blood vessels are essential for proper regulation of blood pressure and the proper functioning of the heart and organs. Aging is accompanied by the accumulation of connective tissue in the vessels, which leads to stiffness of the blood vessels. These stiff blood vessels are a significant cause of high blood pressure and the development of cardiovascular diseases such as heart attacks and strokes. This is particularly important now as people in our Western world are living longer but also want to experience it in good health.
Current treatments are mainly aimed at the function of the two inner layers of the vessel wall and cannot prevent all heart attacks or strokes. We proposed that connective-tissue producing cells in the outer, perivascular cell layer play a causal role in vascular ageing. Therefore, we used advanced technology and identified new gene markers for these perivascular cells.
We use modern technology to study changes in individual cells. With older technology, differences could not be observed because a large mix of whole tissues and all cell types was used. This is similar to a smoothie where the individual fruits cannot be seen anymore. This preliminary work demonstrates that there is indeed an increase in a specific group of connective tissue-producing cells during aging. This has led to the hypothesis that we will now investigate: Reprogramming the function of perivascular cells can reduce damage caused by vascular aging.
We will study perivascular cell function in vivo, in vitro and in interventional studies ex vivo, in so far unimaginable detail. By sophisticated integration of this obtained data, we aim to identify key players promoting vascular ageing and dysfunction and suggest first interventional targets for future therapy to keep our vessels healthy for longer.
Perivascular cell densities and heterogeneity were increased with ageing and associated with collagen accumulation. Deficiency of our new marker for perivascular cells correlated to increased blood pressure in humans and caused hypertension in aged mice with a deficiency of this gene. Vascular stiffness and collagen accumulation was however not affected. In young mice, gene deficiency did not affect vascular function. In cultured cells, the gene deficiency caused heightened oxidative stress thereby changing function of medial cell function and vessel relaxation and contractility. This supports our hypothesis that perivascular cells have a crucial role in vascular function during ageing. Activation of this gene may be a new avenue for treatment of vascular ageing. Results have been shared with scientists, patients, and medical professionals in oral presentations, and will be submitted for publication in a scientific journal within 9 months.
Ageing is currently the main untreated risk factor for cardiovascular diseases, while other treatment of risk factors such as hypercholesterolemia, and hypertension maximally prevent 50% of cardiovascular events such as myocardial infarction or stroke.2 3 As the number of people aged over 70 years reached 1 billion,1 ageing thus represents an unparalleled and neglected contribution to residual risk. In particular, vascular ageing is a major cause of death, increasing the risk of hypertension, atherosclerosis with ensuing heart attacks, and stroke.4 Importantly, it is now recognised that biological vascular age can be adjusted,5, 6 although chronological age marked by date of birth of course cannot change.
The known hallmarks of vascular ageing reflect changes in the two inner layers of the arteries, in the intima and media. Detrimental changes include intimal endothelial cell dysfunction, intima and media thickening, loss of medial vascular smooth muscle cell and elastin, accumulation of medial senescent cells and (mitochondrial) oxidative stress, deposition of medial collagen and/or calcification, together leading to vascular stiffness, loss of compliance and distensibility. The vascular effect of drugs targeting hallmarks of vascular ageing in (pre)clinical models is modest,7-9 and no successful treatment for human vascular ageing exists thus far. Furthermore, changes in the outer perivascular adventitia with human ageing are largely unknown, yet likely impactful. Finding a treatment for vascular ageing requires a better understanding of the early cellular and molecular mechanisms driving both the structural and functional changes of the aged vessel.
We now show in this project that perivascular cell function is crucial for maintaining vascular health during aging. This project thus provides the foundation and background knowledge on perivascular cell function in vascular ageing to lean on in subsequent translational therapeutic and diagnostic developments. Once we know more about the molecular changes in fibroblasts during ageing, a potential therapy will have a durable effect on improving healthy life expectancy, quality of life, and avoiding unnecessary treatments. However, the direct socioeconomic impact of the outcome of this fellowship are limited and the path to actual societal impact is long.
The impact for scientists in my field and other disciplines involving fibroblasts (organ fibrosis, oncology, tissue engineering, scleroderma) is evident as we provide new markers for fibroblasts. These scienctists will be reached via consortia and COST actions I participate in (incl. ERA-CVD, AtheroNL consortium, VascAge and AtheroNET COST action).. This stakeholder group will be informed via conferences, lectures, social media, and publication. Through my role as treasurer of EVBO, and affiliations in Edinburgh University and Aachen University, I will further inform scientists to integrate our new data into scientific practice, such as via the EVBO seminar series, and/or the annual women’s scientist’s festival (Maastricht University). The scientific community will have access to RNAseq data sets in repositories, and papers.
Medical physicians and their patients will also be impacted, and I will discuss future data with cardiovascular patients (Dutch Harteraad organisation) and their physicians how to best reach the target audience, hear what patient groups they feel would benefit, and to stimulate patient participation. I expect to organise workshops/lectures as done before, for instance at the cardiovascular grand rounds, Vascular surgeon network meetings, and hart&vaatcafé Limburg. The general public will be informed via outreach symposia, such as the Maastricht Arts&Science fair, Pint of Science, and/or Kidz college.
Stakeholders in the pharmaceutical industry will benefit from knowledge on biology and will be approached through key contact persons.
The known hallmarks of vascular ageing reflect changes in the two inner layers of the arteries, in the intima and media. Detrimental changes include intimal endothelial cell dysfunction, intima and media thickening, loss of medial vascular smooth muscle cell and elastin, accumulation of medial senescent cells and (mitochondrial) oxidative stress, deposition of medial collagen and/or calcification, together leading to vascular stiffness, loss of compliance and distensibility. The vascular effect of drugs targeting hallmarks of vascular ageing in (pre)clinical models is modest,7-9 and no successful treatment for human vascular ageing exists thus far. Furthermore, changes in the outer perivascular adventitia with human ageing are largely unknown, yet likely impactful. Finding a treatment for vascular ageing requires a better understanding of the early cellular and molecular mechanisms driving both the structural and functional changes of the aged vessel.
We now show in this project that perivascular cell function is crucial for maintaining vascular health during aging. This project thus provides the foundation and background knowledge on perivascular cell function in vascular ageing to lean on in subsequent translational therapeutic and diagnostic developments. Once we know more about the molecular changes in fibroblasts during ageing, a potential therapy will have a durable effect on improving healthy life expectancy, quality of life, and avoiding unnecessary treatments. However, the direct socioeconomic impact of the outcome of this fellowship are limited and the path to actual societal impact is long.
The impact for scientists in my field and other disciplines involving fibroblasts (organ fibrosis, oncology, tissue engineering, scleroderma) is evident as we provide new markers for fibroblasts. These scienctists will be reached via consortia and COST actions I participate in (incl. ERA-CVD, AtheroNL consortium, VascAge and AtheroNET COST action).. This stakeholder group will be informed via conferences, lectures, social media, and publication. Through my role as treasurer of EVBO, and affiliations in Edinburgh University and Aachen University, I will further inform scientists to integrate our new data into scientific practice, such as via the EVBO seminar series, and/or the annual women’s scientist’s festival (Maastricht University). The scientific community will have access to RNAseq data sets in repositories, and papers.
Medical physicians and their patients will also be impacted, and I will discuss future data with cardiovascular patients (Dutch Harteraad organisation) and their physicians how to best reach the target audience, hear what patient groups they feel would benefit, and to stimulate patient participation. I expect to organise workshops/lectures as done before, for instance at the cardiovascular grand rounds, Vascular surgeon network meetings, and hart&vaatcafé Limburg. The general public will be informed via outreach symposia, such as the Maastricht Arts&Science fair, Pint of Science, and/or Kidz college.
Stakeholders in the pharmaceutical industry will benefit from knowledge on biology and will be approached through key contact persons.