PAR-1 and PAR-4 in the experimental periodontal disease

• Grant number: 06/04887-6
• Support Opportunities: Scholarships abroad - Research
• Effective date (Start): February 01, 2007
• Effective date (End): May 31, 2007
• Field of knowledge: Health Sciences - Dentistry - Periodontology
• Principal Investigator: Luis Carlos Spolidorio
• Grantee: Luis Carlos Spolidorio
• Host Investigator: John Lawrence Wallace
• Host Institution: Faculdade de Odontologia (FOAr). Universidade Estadual Paulista (UNESP). Campus de Araraquara. Araraquara , SP, Brazil
• Research place: University of Calgary, Canada

Abstract

Periodontitis and gingivitis are characterized by increased levels of both host and bacterial proteolytic enzymes A diverse range of endogenous chemical mediators orchestrates the host response and controls the inflammatory response. The coagulation cascade is intimately related to inflammation. The coagulation cascade is divided in two ways that converge, culminating in the activation of thrombin and the formation of the fibrin. Classically, thrombin generation is triggered when disruption of vascular integrity allows plasma coagulation factors to contact extravascular tissue factor. Thus, the coagulation cascade provides a mechanism for converting mechanical information in the form of tissue damage and/or vascular leakage into biochemical information in the form of the active protease thrombin. Tissue factor is expressed at low levels on circulating monocytes and leukocyte-derived microparticles. These sources of intravascular tissue factor can be tethered to activated platelets and endothelial cells and concentrated in this way at sites of injury or inflammation. Thrombin regulates platelet aggregation and activation, endothelial cell activation and other important vascular responses, including angiogenesis. A variety of bioactive substances, including growth factors and chemokines, are stored in platelets and released during activation, e.g. VEGF and endostatin, both of which have significant importance in the regulation of angiogenesis. Angiogenesis occurs under physiological and pathological conditions, and contributes to the degree of the inflammation as a result of the ability of new blood vessels to transport proinflammatory cells to the lesion and supply oxygen and nutrients to the inflammad tissue. Angiogenesis is an integral component of the pathogensesis of various disorders such as rheumatoid arthritis, diabetic retinopathy, psoriasis, age-related macular degeneration tumours and periodontitis. Activation of platelets by thrombin is mediated at least in part through cleavage of proteinase-activated receptors (PARs). PARs are G-protein-coupled receptors that use a fascinating mechanism to convert an extracellular proteolytic cleavage event into a transmembrane signal: these receptors carry their own ligands, which are inactive until being until unmasked by proteolytic cleavage. Four distinct PARs have been identified. PAR1 and PAR4 act as receptors for thrombin. Human platelets express PAR1 and PAR4, and activation of either is sufficient to trigger platelet aggregation and secretion. Suggested that endostatin, a potent inhibitor of angiogenesis, is contained within rats platelets and released in response to thrombin via PAR4 in an aggregation-independent manner. This groupfurther demonstrated in rats that pharmacological manipulation of platelet and/or serum levels of VEGF and endostatin resulted in profound effects on healing of gastric ulcers. Suggested that human platelets contain endostatin, and that its release can be triggered by activation of PAR4 but not PAR1. PAR1 activation led to suppression of endostatin release but also to stimulation of the release of a proangiogenic substance, VEGF. PAR4 activation, in contrast, stimulated endostatin release and suppresses release of VEGF. Thus, PAR1 and PAR4 appear to act in a counter-regulatory manner to modulate release of factors regulating angiogenesis. Thereafter, several studies have demonstrated that systemic administration of recombinant endostatin , produced and delivered by varying means, efficiently blocks angiogenesis. VEGF is an endothelial-specific growth factor that potently increases microvascular permeability; stimulates endothelial cell proliferation; induces proteolytic enzyme expression; and the migration of endothelial cell, monocytes, and osteoblasts, all of which are essencial for angiogenesis. An imbalance in the production of antiangiogenic versus proangiogenic factors could result in impaired angiogenesis and wound healing. (AU)