Role of perivascular adipose tissue on vascular damage in hypertension: focus on fibrosis and calcification
Perivascular adipose tissue (PVAT) is central to the development of hypertension especially in obese individuals in which the amount of visceral PVAT is markedly increased. We hypothesize that phenotypic alterations in PVAT lead to an enhanced expression of osteogenic factors, leading to vascular remodeling, calcification and arterial stiffness. ESR15 aims to elucidate the role of PVAT-derived osteogenic factors, angiotensin AT2 receptors, exosomes, oxidative stress, and inflammation on vascular alterations associated with hypertension.
ESR15 will be seconded in the Schalkwijk lab at UM, for determination of the osteogenic marker profile in PVAT from hypertensive rats and humans with multi-array technology (2 months). 2. In the Stehouwer/Greevenbroek/Houben groups at UM, ESR15 will analyze the presence of metabolites identified by ESR2 in PVAT and PVAT-derived exosomes from hypertensive rats and humans (2 months). 3. ESR15 will be trained at Attoquant on LC-MS/MS-based analysis of renin-angiotensin sysyem components in PVAT and vascular tissue (1 month), and at Intelligent Imaging on PVAT whole volume preparation for pro-osteoblast imaging (2 separate fortnights). TMC Data Science will support ESR15 with patient data analyses (multivariate variables) for development and validation of a predictive model (ESR4).
1. We will use two rat models of hypertension: the SHR (spontaneously hypertensive rat), a genetic model of hypertension, and the MWF (Münster Wistar Frömter rat), a model of hypertension associated to chronic kidney disease. These models will be subjected to high-fat diet to induce obesity. In addition, we will characterize samples of omental adipose tissue from hypertensive obese patients submitted to bariatric surgery for isolation of PVAT, PVAT-derived exosomes and resistance arteries (rat and human omental). 2. Vascular smooth muscle cells (VSMCs) will be cultured with plasma from rat/humans and/or PVAT-derived exosomes to evaluate VSMCs transdifferentiation into osteoblast-like cells through alterations in the expression pattern of osteogenic and calcification markers. 3. PVAT and PVAT-derived exosomes from both rats and humans will be analyzed for alterations in gene and protein expression profiles of osteogenic factors, metabolic factors, inflammatory markers and reactive oxygen species. 4. Vascular function, structure and mechanics will be assessed in rat and human isolated arteries. We will characterize MMP-2/-9 activation, MMP-TIMP interaction and extracellular matrix turnover (elastin/collagen). 5. Markers will be analyzed in peripheral blood mononuclear cells (PBMCs) from hypertensive rats/patients and correlated with pulse wave velocity, renin-angiotensin system activity, oxidative stress and inflammatory markers.
- Qualifications: Master degree in the field of Pharmaceutical Sciences/Pharmacology, Biology, Molecular Biology, or a related discipline (graduation date before project start date);
- Experience: cell culture, biochemical and molecular biology techniques; vascular function techniques, image analysis and animal handling is of added value.
- Knowledge & skills: excellent theoretical background in vascular biology and cardiovascular physiology/pharmacology, statistics, excellent knowledge in statistics, interest in imaging techniques and complex data analyses.
- Abilities: the applicant should be able to perform team-oriented as well as independent work: good communication and interpersonal skills to organize research with both academics and professionals; good communication (verbal and writing) skills in English; confirmed capacity to write high-level scientific reports and papers; interested in participating in educational tasks; independent and creative team player.
- Attitude and disposition: adaptability to different labs, disponibility for traveling and mobility