Platelet Bone Morphogenetic Protein-4 Mediates Vascular Inflammation and Neointima Formation after Arterial Injury

• Main Authors: Marietta Jank, Nikolaus von Niessen, Christoph B. Olivier, Hannah Schmitt, Nathaly Anto-Michel, Ingo Hilgendorf, Christoph Bode, Martin Moser, Jennifer S. Esser, Qian Zhou
• Format: Article
• Language: English
• Published: MDPI AG 2021-08-01
• Series: Cells
• Subjects: BMP; platelet; restenosis; inflammation
• Online Access: https://www.mdpi.com/2073-4409/10/8/2027

The purpose of this study is to investigate the role of platelet bone morphogenetic proteins (BMP)-4 during vascular inflammation and remodeling in a mouse model of carotid wire injury. Transgenic mice with a platelet-specific deletion of BMP-4 (<i>BMP4^Plt−/−</i>) were generated. Intravital microscopy was performed to evaluate leukocyte adhesion to the vessel wall. Expression of adhesion molecules and chemokines were analyzed. Platelet-leukocyte aggregates (PLAs) were evaluated using flow cytometry. For carotid wire injury, <i>BMP4^Plt</i>^−/− mice were further crossed with LDLr^−/− mice (<i>BMP4^Plt−/−/LDLr^−/−</i>) and fed with a high cholesterol diet for 2-weeks. Carotid wire injury was performed, and re-endothelialization and neointimal formation were evaluated. In comparison to the control mice, stimulation with TNFα resulted in fewer rolling and adherent leukocytes to the vessel wall in the <i>BMP4^Plt−/−</i> mice. mRNA and protein expression of P-selectin and adhesion molecules were reduced in the aorta of the <i>BMP4^Plt−/−</i> mice. In platelets from the <i>BMP4^Plt−/−</i> mice, the expression of P-selectin was reduced, and fewer PLA formations were measured than in the control mice. Loss of platelet BMP-4 further prevented neointima formation after carotid wire injury. Endothelial regeneration after injury was decelerated in the <i>BMP4^Plt−/−</i> mice, and confirmed in-vitro, where the deletion of platelet BMP-4 inhibited endothelial cell proliferation and migration. We demonstrate for the first time that platelet BMP-4 is involved during vascular inflammation and remodeling. This is partially mediated by the inhibition of platelet activation, reduced expression of adhesion molecules and inflammatory responses. Our findings identify platelet BMP-4 as a mediator of vascular inflammation in early atherosclerosis and restenosis.