Chronic high fat diet-induced cerebrovascular remodeling impairs recovery of blood flow after cerebral ischemia in mice

Abstract

Obesity and associated metabolic disturbances worsen brain ischemia outcome. High fat diet (HFD)-fed mice are obese and have cerebrovascular remodeling and worsened brain ischemia outcome. We determined whether HFD-induced cerebrovascular remodeling impaired reperfusion to the ischemic penumbra. Six-week-old C57BL/6J or matrix metalloprotease-9 knockout (MMP-9^−/−) mice were on HFD or regular diet (RD) for 12 to 14 months before a 60-min left middle cerebral arterial occlusion (MCAO). Photoacoustic microscopy was performed at left cerebral frontal cortex. HFD increased cerebrovascular density and tortuosity in C57BL/6J mice but not in MMP-9^−/− mice. Blood flow to the ischemic penumbra slowly recovered but did not reach the baseline 2 h after MCAO in RD-fed mice. Oxygen extraction fraction was increased to maintain cerebral metabolic rate of oxygen (CMRO₂) throughout brain ischemia and reperfusion period. This blood flow recovery was worsened in HFD-fed mice, leading to decreased CMRO₂. MMP-9^−/− attenuated these HFD effects. HFD increased MMP-9 activity and interleukin 1β. Pyrrolidine dithiocarbamate, an anti-inflammatory agent, abolished the HFD effects. Interleukin 1β increased MMP-9 activity. In summary, HFD induces cerebrovascular remodeling, leading to worsened recovery of blood supply to the ischemic penumbra to contribute to poor outcome after brain ischemia. Neuroinflammation may activate MMP-9 in HFD-fed mice.