Critical role of matrix metalloprotease-9 in chronic high fat diet-induced cerebral vascular remodelling and increase of ischaemic brain injury in mice†

Cardiovasc Res. 2014 Sep 1;103(4):473-84. doi: 10.1093/cvr/cvu154. Epub 2014 Jun 15.


Aims: About one-third of American adults and 20% of teenagers are obese. Obesity and its associated metabolic disturbances including hyperlipidaemia are risk factors for cardiovascular diseases including stroke. They can worsen neurological outcome after stroke. We determined whether obesity and hyperlipidaemia could induce cerebral vascular remodelling via matrix metalloproteases (MMP) and whether this remodelling affected neurological outcome after brain ischaemia.

Methods and results: Six-week-old male CD1, C57BL/6J, and MMP-9(-/-) mice were fed regular diet (RD) or high-fat diet (HFD) for 10 weeks. They were subjected to vascular casting or a 90 min middle cerebral arterial occlusion (MCAO). Mice on HFD were heavier and had higher blood glucose and lipid levels than those on RD. HFD-fed CD1 and C57BL/6J mice had an increased cerebral vascular tortuosity index and decreased inner diameters of the middle cerebral arterial root. HFD increased microvessel density in CD1 mouse cerebral cortex. After MCAO, CD1 and C57BL/6J mice on HFD had a bigger infarct volume, more severe brain oedema and blood-brain barrier damage, higher haemorrhagic transformation rate, greater haemorrhagic volume, and worse neurological function. HFD increased MMP-9 activity in the ischaemic and non-ischaemic brain tissues. Although HFD increased the body weights, blood glucose, and lipid levels in the MMP-9(-/-) mice on a C57BL/6J genetic background, the HFD-induced cerebral vascular remodelling and worsening of neurological outcome did not occur in these mice.

Conclusion: HFD induces cerebral vascular remodelling and worsens neurological outcome after transient focal brain ischaemia. MMP-9 activation plays a critical role in these HFD effects.

Keywords: Cerebral vascular remodelling; High fat diet; Ischemic stroke; Matrix metalloprotease; Mouse.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Blood Glucose / physiology
  • Brain Injuries / enzymology*
  • Brain Ischemia / enzymology*
  • Diet, High-Fat / adverse effects*
  • Disease Models, Animal
  • Male
  • Matrix Metalloproteinase 9 / deficiency
  • Matrix Metalloproteinase 9 / metabolism*
  • Mice
  • Mice, Knockout
  • Obesity / complications*
  • Obesity / metabolism
  • Vascular Remodeling / physiology*


  • Blood Glucose
  • Matrix Metalloproteinase 9
  • Mmp9 protein, mouse