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Pulmonary Arterial Remodelling By Caglayan et al. Respiratory Research (2019) 20:42 https://doi.org/10.1186/s12931-019-1003-4 RESEARCH Open Access Pulmonary arterial remodelling by deficiency of peroxisome proliferator- activated receptor-γ in murine vascular smooth muscle cells occurs independently of obesity-related pulmonary hypertension Evren Caglayan1,2,6, Manuela Trappiel3, Arnica Behringer1,2, Eva Maria Berghausen1, Margarete Odenthal4, Ernst Wellnhofer5 and Kai Kappert 3,7* Abstract Background: Obesity is associated with cardiovascular complications, including pulmonary hypertension (PH). Reports suggest that peroxisome proliferator-activated receptor-γ (PPARγ) has direct action in preventing vascular remodelling in PH. Here we dissected the specific role of high-fat-diet (HFD)-induced obesity and vascular smooth muscle cell (VSMC)-PPARγ for remodelling of small pulmonary arteries. Methods: Wild-type (WT) and VSMC-specific PPARγ-knockout (SmPparγ−/−) mice were fed a low-fat-diet (LFD, 10% kcal from fat) or HFD (60% kcal from fat) for 24 weeks. Mice were metabolically phenotyped (e.g. weight development, insulin/glucose tolerance) at the beginning, and after 12 and 24 weeks, respectively. At 24 weeks additionally pulmonary pressure, heart structure, pulmonary vascular muscularization together with gene and protein expression in heart and lung tissues were determined. Results: HFD increased right ventricular systolic pressure (RVSP) to a similar extent in WT and SmPparγ−/− mice. HFD decreased glucose tolerance and insulin sensitivity in both WT and SmPparγ−/− mice. Importantly, the increase in RVSP correlated with the degree of insulin resistance. However, VSMC-PPARγ deficiency increased pulmonary vascular muscularization independently of the diet-induced rise in RVSP. This increase was associated with elevated expression of early growth response protein 1 in heart and osteopontin in lung tissue. Conclusions: Here we demonstrate a correlation of insulin resistance and pulmonary pressure. Further, deficiency of PPARγ in VSMCs diet-independently leads to increased pulmonary vascular muscularization. Keywords: Pulmonary hypertension, VSMC, PPARgamma, Insulin resistance, Obesity Background [1, 2]. These changes lead to a progressive increase in Pulmonary arterial hypertension (PAH) is a disease of pulmonary vascular resistance, which results in elevated the small pulmonary arteries that involves vascular pro- pulmonary artery pressure of ≥25 mmHg, right ventricu- liferation, remodelling, vasoconstriction and thrombosis lar failure and premature death in humans [3, 4]. Cells within the vessel wall, including vascular smooth muscle * Correspondence: [email protected] cells (VSMCs), trigger, sustain and regulate these remod- 3Berlin Institute of Health, Institute of Laboratory Medicine, Clinical Chemistry elling processes [5]. PAH occurs genetically [6–8], idio- and Pathobiochemistry, Center for Cardiovascular Research (CCR), Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, pathically or secondary after e.g. heart failure, chronic Humboldt-Universität zu Berlin, Berlin, Germany lung disease, pulmonary embolism [3]. To date, no curing 7DZHK (German Centre for Cardiovascular Research), partner site Berlin, approach has been established, thus, patients are treated Berlin, Germany Full list of author information is available at the end of the article symptomatically to improve their quality of life [3]. © The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Caglayan et al. Respiratory Research (2019) 20:42 Page 2 of 14 Clinical and experimental observations suggest a floxed PPARγ mice [22]. Eight to 12 week old littermate − − connection between obesity, insulin resistance and male WT (Cre-) and SmPparγ / (Cre+) mice on a VSMC-driven vascular remodelling including PAH [9, 10], mixed genetic background (C57BL/6, SJL, DBA/2J, C3H) − − while the molecular mechanisms remain elusive. Patients were randomized as follows: WT and SmPparγ / fed ad characterized with PAH were shown to be more over- libitum a low-fat diet (LFD) (10% kcal from fat; Brogaar- weight [11]. Obesity also triggers comorbidities such as den, Gentofte, Denmark; D12450J) and WT and − − obstructive sleep apnea (OSA) and obesity hypoventila- SmPparγ / fed ad libitum a high-fat diet (HFD) (60% tion syndrome (OHS) in patients, directly or indirectly kcal from fat; Brogaarden; D12492) for 24 weeks. Mice impacting PAH. Indeed, the prevalence of PAH in were housed at room temperature with a 12 h light/dark patients with obesity has been reported ranging from cycle. After sacrificing, organs were excised, weighed, 20 to 47% (body-mass-index of 32 kg/m2 and 37 kg/m2, shock-frozen in liquid nitrogen and stored at − 80 °C respectively) [11–13]. Whether diabetes contributes to until further investigation. the risk for PAH or vice versa is a matter of debate. Nonetheless, compared to the overall population, pa- Metabolic phenotyping (body weight, food intake, tients with insulin resistance or diabetes have a doubled glucose tolerance test, insulin tolerance test), right risk to develop PAH [9, 10]. Further, patients with PAH ventricular systolic pressure and systemic blood pressure and diabetes have a significantly reduced walking cap- Body weight was measured twice weekly throughout the acity (six-minutes walking distance), reduced survival study. Food and water intake were measured for up to and increased risk for pulmonary venous disease with 24 h in a LabMaster (TSE Systems; Bad Homburg, hemodynamics suggesting higher right ventricular dia- Germany) after 12 weeks and at the end of the experi- stolic dysfunction. Moreover, diabetics are character- ment (24 weeks). At the beginning and after 12 and 24 ized by significantly higher prevalence of pulmonary weeks, intraperitoneal (i.p.) insulin tolerance tests (ITT) embolism [14]. using a dose of 0.5 U/kg insulin (Insuman® Rapid, Sanofi In lung tissue of patients with PAH the expression of Aventis, Berlin, Germany) and i.p. glucose tolerance tests peroxisome proliferator-activated receptor-γ (PPARγ)is (GTT) with 1 g/kg glucose (Glucosteril, Fresenius, Bad reduced [15–17]. Moreover, PPARγ agonists have been Homburg, Germany) were carried out in ~ 4 h and ~ 12 established in anti-diabetic treatment with beneficial im- h fasted mice, respectively. Right ventricular systolic pact on vascular remodelling [18, 19]. pressure (RVSP), a measure for pulmonary arterial sys- Pharmacological activation of PPARγ in VSMCs was tolic pressure (PASP), was recorded with a Millar® shown to decrease their proliferation and migration [20]. microtip catheter (SPR1000), which was inserted into Furthermore, in vitro experiments demonstrated that the right ventricle (RV) through the jugular vein. Sys- insulin is able to maintain VSMCs quiescence and coun- temic arterial pressure (SAP) was measured in the teracting growth factor induced dedifferentiation via the carotid artery. The catheter signal was amplified using a phosphoinositide 3-kinase (PI3K) pathway [21]. On the PowerLab® amplifier and converted to corresponding other hand, insulin promotes VSMC migration. During pressure curves using LabChart7® software (AD Instru- insulin resistance, PI3K signaling is impaired, which may ments, Sydney, Australia). To determine the individual impact on pulmonary vascular remodelling and de novo SAP and RVSP three to five tracings at different time muscularization of non-muscularized small vessels. points were used. While activation of PPARγ restores insulin signaling, the impact of PPARγ in VSMCs in obesity-related pulmon- Lung tissue preparation and morphometric analysis ary remodelling has not been determined in detail. Lungs were perfused with ice cold phosphate buffered The purpose of the study was to address the role of saline (PBS) and subsequently with 1% paraformaldehyde PPARγ in VSMCs in a model of high fat-diet (HFD) in- (PFA), extracted and fixed in 4% PFA. After dehydration, duced obesity. Therefore, we evaluated the impact of lungs were embedded in paraffin using standard proce- HFD on right ventricular systolic pressure (RVSP), pul- dures. To quantify the degree of muscularization of monary muscularization and metabolic changes in WT pulmonary arteries, 3 μm tissue sections were stained for − − and SmPparγ / mice. α-smooth muscle actin (Sigma-Aldrich, #2547) and von Willebrand factor (Dako, A0082) using standard immu- Methods nohistochemical protocols. The degree of musculariza- Animals tion was defined by α-smooth muscle actin positive − − SmPparγ / mice were generated using transgenic mice parts as percentage of the total pulmonary artery cross expressing Cre-recombinase under the control of the section: non-muscularized: < 25%, muscularized: ≥ 25%. smooth muscle protein 22-alpha promotor (The Jackson Data are shown as ratio of muscularized to non-muscu- Laboratory, Bar Harbor, Maine) and homozygously larized arteries. Furthermore, the medial wall thickness Caglayan et al. Respiratory Research
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