Resolvin D2 prevents vascular remodeling, hypercontractility and endothelial dysfunction in obese hypertensive mice through modulation of vascular and proinflammatory factors

• Published in: Biomedicine & pharmacotherapy Vol. 174; p. 116564
• Main Authors: Rodrigues-Diez, Raquel, Ballesteros-Martinez, Constanza, Moreno-Carriles, Rosa María, Nistal, Francisco, Díaz del Campo, Lucía S., Cachofeiro, Victoria, Dalli, Jesmond, García-Redondo, Ana B., Redondo, Juan M., Salaices, Mercedes, Briones, Ana M.
• Format: Journal Article
• Language: English
• Published: France Elsevier Masson SAS 01-05-2024; Elsevier
• Subjects: Angiotensin II; Animals; Aortic Aneurysm, Abdominal - drug therapy; Aortic Aneurysm, Abdominal - metabolism; Aortic Aneurysm, Abdominal - pathology; Diet, High-Fat - adverse effects; Disease Models, Animal; Docosahexaenoic Acids - pharmacology; Endothelial dysfunction; Endothelium, Vascular - drug effects; Endothelium, Vascular - metabolism; Endothelium, Vascular - pathology; Humans; Hypertension; Hypertension - drug therapy; Hypertension - metabolism; Inflammation - metabolism; Inflammation - pathology; Inflammation Mediators - metabolism; Macrophages - drug effects; Macrophages - metabolism; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Obesity - complications; Obesity - metabolism; Resolution of inflammation; Resolvin D2; vascular remodeling; Vascular Remodeling - drug effects; Vasoconstriction - drug effects; MRI; SPMs; HFD; GLM; SPE; PFA; WAT; Phe; vascular remodeling; BSA; LC-MS/MS; MA; FBS; KHS; Endothelial dysfunction; PVAT; AngII; WT; BMI; MaR; IFNγ; PBS; RvE; Hypertension; AAA; RvD; Obesity; Resolvin D2; Resolution of inflammation; EGF; PUFA; LXs; ALOXs; ISG15; IL-1β; PBMC; ECM; MoDM; CTA; TNF-α; BLT1; DEA-NO; VSMC; HMEC-1; PDs
• ISSN: 0753-3322; 1950-6007
• DOI: 10.1016/j.biopha.2024.116564

During resolution of inflammation, specialized proresolving mediators (SPMs), including resolvins, are produced to restore tissue homeostasis. We hypothesized that there might be a dysregulation of SPMs pathways in pathological vascular remodeling and that resolvin D2 (RvD2) might prevent vascular remodeling and contractile and endothelial dysfunction in a model of obesity and hypertension. In aortic samples of patients with or without abdominal aortic aneurysms (AAA), we evaluated gene expression of enzymes involved in SPMs synthesis (ALOXs), SPMs receptors and pro-inflammatory genes. In an experimental model of aortic dilation induced by high fat diet (HFD, 60%, eighteen weeks) and angiotensin II (AngII) infusion (four weeks), we studied the effect of RvD2 administration in aorta and small mesenteric arteries structure and function and markers of inflammation. In human macrophages we evaluated the effects of AngII and RvD2 in macrophages function and SPMs profile. In patients, we found positive correlations between AAA and obesity, and between AAA and expression of ALOX15, RvD2 receptor GPR18, and pro-inflammatory genes. There was an inverse correlation between the expression of aortic ALOX15 and AAA growth rate. In the mice model, RvD2 partially prevented the HFD plus AngII-induced obesity and adipose tissue inflammation, hypertension, aortic and mesenteric arteries remodeling, hypercontratility and endothelial dysfunction, and the expression of vascular proinflammatory markers and cell apoptosis. In human macrophages, RvD2 prevented AngII-induced impaired efferocytosis and switched SPMs profile. RvD2 might represent a novel protective strategy in preventing vascular damage associated to hypertension and obesity likely through effects in vascular and immune cells.
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•GPR18 and ALOX15 are upregulated in human abdominal aortic aneurysms.•Human aortic ALOX15 negatively correlates with abdominal aortic aneurysms growth.•RvD2 partially prevents obesity and hypertension in obese hypertensive mice.•RvD2 partially prevents vascular remodeling in obese hypertensive mice.•RvD2 prevents endothelial dysfunction in obese hypertensive mice.