Myeloid p53 regulates macrophage polarization and venous thrombus resolution by inflammatory vascular remodeling in mice.
Deep venous thrombosis (DVT) remains a common and serious cardiovascular problem with both fatal and long-term consequences. The consequences of DVT include the development of postthrombotic syndrome in 25% to 60% of DVT patients. Despite the clinical importance of venous thrombus resolution, the cellular and molecular mediators involved are poorly understood, and currently there is no molecular therapy to accelerate this process. Several lines of evidence suggest that a complex and interrelated array of molecular signaling processes are involved in the inflammatory vascular remodeling associated with the resolution of DVT. Here, we have identified a role for the tumor suppressor gene p53 in regulating venous thrombus resolution. Using the stasis model of venous thrombosis and resolution in mice, we found that genetic deficiency of p53 or pharmacologic inhibition by pifithrin impairs thrombus resolution and is associated with increased fibrosis and altered expression of matrix metalloproteinase-2. The effect of p53 loss was mediated by cells of the myeloid lineage, resulting in enhanced polarization of the cytokine milieu toward an M1-like phenotype. Furthermore, augmentation of p53 activity using the pharmacological agonist of p53, quinacrine, accelerates venous thrombus resolution in a p53-dependent manner, even after establishment of thrombosis. Together, these studies define mechanisms by which p53 regulates thrombus resolution by increasing inflammatory vascular remodeling of venous thrombi in vivo, and the potential therapeutic application of a p53 agonist as a treatment to accelerate this process in patients with DVT.
Center for Vascular and Inflammatory Diseases.|Department of Surgery, and.|Department of Physiology, University of Maryland School of Medicine, Baltimore, MD; and.
Subhradip
S
Mukhopadhyay
Center for Vascular and Inflammatory Diseases.|Department of Surgery, and.|Department of Physiology, University of Maryland School of Medicine, Baltimore, MD; and.
Toni M
TM
Antalis
Department of Surgery, University of California, San Francisco, San Francisco, CA.
Khanh P
KP
Nguyen
Center for Vascular and Inflammatory Diseases.|Department of Surgery, and.|Department of Physiology, University of Maryland School of Medicine, Baltimore, MD; and.
Mark H
MH
Hoofnagle
Center for Vascular and Inflammatory Diseases.|Department of Surgery, and.|Department of Physiology, University of Maryland School of Medicine, Baltimore, MD; and.
Rajabrata
R
Sarkar
D000818:Animals; D004195:Disease Models, Animal; D005355:Fibrosis; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D008264:Macrophages / Q000378:metabolism* / Q000473:pathology; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis; D051379:Mice; D011796:Quinacrine / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D066253:Vascular Remodeling; D020246:Venous Thrombosis / Q000378:metabolism* / Q000473:pathology
D016159:Tumor Suppressor Protein p53; D020778:Matrix Metalloproteinase 2; C522362:Mmp2 protein, mouse; D011796:Quinacrine