Regulatory role of prostaglandins on the neovascularization process during the regeneration of skeletal muscular tissue

• Grant number: 20/05269-1
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Effective date (Start): December 01, 2020
• Effective date (End): February 28, 2022
• Field of knowledge: Biological Sciences - Pharmacology
• Principal Investigator: Vanessa Moreira
• Grantee: Melissa Rodrigues Correia
• Host Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil

Abstract

The regeneration process of skeletal muscle tissue, after injury, consists of finely orchestrated events and regulated by several factors, highlighting the inflammatory process that accompanies from the injury to the remodeling of tissue components. However, if the regeneration process is unable to proceed in an organized manner, the regeneration of muscle fibers will be fail, with intense formation of fibrosis, leading to loss of muscle function. One of the crucial factors for the quality of tissue repair is the restoration of local microcirculation, essential for supply of oxygen and nutrients, in addition to the removal of metabolites and cellular debris from the site of muscle tissue regeneration. However, besides the knowledge of the factors that directly regulate the angiogenesis process, such as the classic vascular endothelial growth factor (VEGF), little is understood about the influence of pro-inflammatory mediators in this phenomenon, since they are known to act on the various transcriptional, molecular and cellular components involved in the regeneration process of skeletal muscle tissue. Among the inflammatory mediators, we highlight the lipid mediators derived from arachidonic acid, in particular prostaglandins generated from the cyclooxygenase (COX) pathway, which are known to act in the proliferation of myogenic cells and in regulating the process of their differentiation for the formation new muscle fibers. However, the effect of prostaglandins on tissue neovascularization on the occasion of skeletal muscle tissue regeneration after injury is still poorly understood. On the other hand, the use of Bothrops snake venoms can be complex models for application in muscle regeneration studies, since these venoms contain myotoxic toxins and others that compromise the structure of blood vessels, thus affecting the quality of muscle tissue restoration. Thus, the present study aims to investigate the role of prostaglandins on the neovascularization of muscle tissue, at the time of muscle tissue regeneration, in a myotoxicity model, induced by Bothrops asper venom, and the administration or not of selective and non-selective inhibitors for COX-1 and COX-2, as: (I) morphological / histological changes; (II) expression profile of COX-1 and 2 and of neovascularization markers such as CD3 and collagen IV; (III) for the production of VEGF and metalloproteinases; (IV) the degree of hemorrhage and; (V) the degree of restoration of tissue blood perfusion The comprehension of the influence of prostaglandins on neovascularization, will complement the knowledge of the role of these lipid mediators on the muscle regeneration process. Furthermore, this study will contribute to the discovery of new therapeutic targets that aim at the quality of skeletal muscle tissue regeneration, after injury.