Perivascular Adipose Tissue-Derived PDGF-D Contributes to Aortic Aneurysm Formation During Obesity

Diabetes. 2018 Aug;67(8):1549-1560. doi: 10.2337/db18-0098. Epub 2018 May 24.

Abstract

Obesity increases the risk of vascular diseases, including aortic aneurysm (AA). Perivascular adipose tissue (PVAT) surrounding arteries are altered during obesity. However, the underlying mechanism of adipose tissue, especially PVAT, in the pathogenesis of AA is still unclear. Here we showed that angiotensin II (AngII) infusion increases the incidence of AA in leptin-deficient obese mice (ob/ob) and high-fat diet-induced obese mice with adventitial inflammation. Furthermore, transcriptome analysis revealed that platelet-derived growth factor-D (PDGF-D) was highly expressed in the PVAT of ob/ob mice. Therefore, we hypothesized that PDGF-D mediates adventitial inflammation, which provides a direct link between PVAT dysfunction and AA formation in AngII-infused obese mice. We found that PDGF-D promotes the proliferation, migration, and inflammatory factors expression in cultured adventitial fibroblasts. In addition, the inhibition of PDGF-D function significantly reduced the incidence of AA in AngII-infused obese mice. More importantly, adipocyte-specific PDGF-D transgenic mice are more susceptible to AA formation after AngII infusion accompanied by exaggerated adventitial inflammatory and fibrotic responses. Collectively, our findings reveal a notable role of PDGF-D in the AA formation during obesity, and modulation of this cytokine might be an exploitable treatment strategy for the condition.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adventitia / drug effects
  • Adventitia / immunology
  • Adventitia / metabolism
  • Adventitia / pathology
  • Angiotensin II / administration & dosage
  • Angiotensin II / adverse effects
  • Animals
  • Aorta, Abdominal / diagnostic imaging
  • Aorta, Abdominal / drug effects
  • Aorta, Abdominal / metabolism*
  • Aorta, Abdominal / pathology
  • Aortic Aneurysm, Abdominal / diagnostic imaging
  • Aortic Aneurysm, Abdominal / etiology*
  • Aortic Aneurysm, Abdominal / metabolism
  • Aortic Aneurysm, Abdominal / pathology
  • Benzimidazoles / pharmacology
  • Cells, Cultured
  • Diet, High-Fat / adverse effects
  • Drug Implants
  • Gene Expression Regulation / drug effects
  • Inflammation Mediators / metabolism
  • Intra-Abdominal Fat / drug effects
  • Intra-Abdominal Fat / immunology
  • Intra-Abdominal Fat / metabolism*
  • Intra-Abdominal Fat / pathology
  • Lymphokines / agonists
  • Lymphokines / antagonists & inhibitors
  • Lymphokines / genetics
  • Lymphokines / metabolism*
  • Male
  • Mice
  • Mice, Mutant Strains
  • Mice, Transgenic
  • Obesity / etiology
  • Obesity / metabolism
  • Obesity / pathology
  • Obesity / physiopathology*
  • Organ Specificity
  • Platelet-Derived Growth Factor / agonists
  • Platelet-Derived Growth Factor / antagonists & inhibitors
  • Platelet-Derived Growth Factor / genetics
  • Platelet-Derived Growth Factor / metabolism*
  • Quinolines / pharmacology
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / metabolism
  • Subcutaneous Fat, Abdominal / drug effects
  • Subcutaneous Fat, Abdominal / immunology
  • Subcutaneous Fat, Abdominal / metabolism
  • Subcutaneous Fat, Abdominal / pathology
  • Survival Analysis

Substances

  • Benzimidazoles
  • CP-673,451
  • Drug Implants
  • Inflammation Mediators
  • Lymphokines
  • Pdgfd protein, mouse
  • Platelet-Derived Growth Factor
  • Quinolines
  • Recombinant Proteins
  • Angiotensin II