Abstract
LRP1-pPyk2 axis is essential for the upregulatory effect of hypoxia on MMP-9 activation and human VSMC (hVSMC) migration. Currently, there are not efficient models for the translational study of atherosclerosis. The morphological and physiological features of atherosclerosis are different between human and animal models, particularly in mouse models. Therefore, the aim of current investigation was to compare the effect of hypoxia on LRP1-Pyk2-MMP-9 axis in human and mouse vascular smooth muscle cells (mVSMC) and its consequences on VSMC migration. We demonstrated that hypoxic modulation of LRP1-pPyk2-MMP-9 axis is opposite between hVSMC and mVSMC. The modulation of LRP1/pPyk2 levels by hypoxia is positive in hVSMC but negative in mVSMC. We showed that the inverse effect of LRP1/pPyk2 axis is associated with a differential effect of hypoxia on MMP-9 expression and activation. Hypoxia-induced MMP-9 activation was concomitant with an increased hVSMC migratory capacity. Surprisingly, mVSMC migrate under hypoxic conditions despite the downregulatory effect of hypoxia on MMP-9 expression or activation. Our results highlight the crucial role of LRP1-pPyk2-MMP-9 axis in vascular cell migration. In addition, we propose that the extrapolation of results from animal models to humans is not suitable for this specific mechanism in hypoxia-related vascular conditions.
Highlights
Atherosclerosis is included in a group of diseases that share pathophysiological mechanisms linked to the deregulation of vascular extracellular matrix remodeling in response to hypoxia [1]
We have previously shown that human Vascular smooth muscle cells (VSMC) internalize huge amounts of cholesterol esters from aggregated LDL through low density lipoprotein receptor-related protein 1 (LRP1) upregulation [3]
Phosphorylated proline-rich tyrosine kinase 2 (Pyk2) (Figures 1(e) and 1(g)) and LRP1 (Figures 1(e) and 1(f)) protein levels were significantly decreased at 16 and 32 hours in mouse vascular smooth muscle cells (mVSMC) exposed to hypoxia
Summary
Atherosclerosis is included in a group of diseases that share pathophysiological mechanisms linked to the deregulation of vascular extracellular matrix remodeling in response to hypoxia [1]. Vascular smooth muscle cells (VSMC) are one of the main cellular determinants of arterial wall pathology. These cells play a crucial role in the modulation of extracellular matrix composition. VSMC modify extracellular matrix altering protein synthesis or degradation in response to atherogenic stimuli [2]. The arterial wall integrity is importantly affected by the balance between VSMC migration and proliferation. This balance is fundamental for intimal thickening
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