title: Pathology of human plaque vulnerability: mechanisms and consequences of intraplaque haemorrhages.
abstract: Atherothrombotic diseases are still major causes of inability and mortality and fighting atherothrombosis remains a public health priority. The involvement of repeated intraplaque haemorrhages (IPH) in the evolution of atherothrombotic lesions towards complications was proposed as early as 1936. This important topic has been recently revisited and reviewed. Histological observations have been corroborated by magnetic resonance imaging (MRI) of human carotid atheroma, identifying IPH as the main determinant of plaque evolution towards rupture. Beside the intimal integration of asymptomatic luminal coagulum, inward sprouting of neovessels from the adventitia towards the plaque, is one source of IPH in human atheroma. We recently described that directed neo-angiogenesis from the adventitia towards the plaque, across the media, is initiated by lipid mediators generated by the plaque on the luminal side, outwardly convected to the medial VSMCs. Subsequent stimulation of VSMC PPAR-γ receptors induces VEGF expression which causes centripetal sprouting of adventitial vessels. However, this neovascularization is considered to be immature and highly susceptible to leakage. The main cellular components of IPH are Red Blood Cells (RBCs), which with their haemoglobin content and their cell membrane components, particularly enriched in unesterified cholesterol, participate in both the oxidative process and cholesterol accumulation. The presence of iron, glycophorin A and ceroids provides evidence of RBCs. IPH also convey blood leukocytes and platelets and are sites prone to weak pathogen contamination. Therefore prevention and treatment of the biological consequences of IPH pave the way to innovative preventive strategies and improved therapeutic options in human atherothrombotic diseases.
authors.affiliation: UMR 1148 Inserm-Paris7 University, Xavier Bichat Hospital, 75018 Paris, France. Electronic address: Jean-Baptiste.Michel@inserm.fr.
authors.forename: Jean-Baptiste
authors.initials: JB
authors.lastname: Michel
authors.affiliation: Vascular Research Lab, Fundación Jiménez Díaz-Autonoma University, Madrid, Spain.
authors.forename: José Luis
authors.initials: JL
authors.lastname: Martin-Ventura
authors.affiliation: UMR 1148 Inserm-Paris7 University, Xavier Bichat Hospital, 75018 Paris, France.
authors.forename: Antonino
authors.initials: A
authors.lastname: Nicoletti
authors.affiliation: UMR 1148 Inserm-Paris7 University, Xavier Bichat Hospital, 75018 Paris, France.
authors.forename: Benoit
authors.initials: B
authors.lastname: Ho-Tin-Noé
mesh_terms: D042501:Angiogenic Proteins / Q000378:metabolism; D001158:Arteries / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D050197:Atherosclerosis / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D015415:Biomarkers / Q000378:metabolism; D018450:Disease Progression; D004912:Erythrocytes / Q000378:metabolism; D006470:Hemorrhage / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D006801:Humans; D057054:Molecular Imaging / Q000379:methods; D009389:Neovascularization, Pathologic; D058226:Plaque, Atherosclerotic; D012307:Risk Factors; D012422:Rupture, Spontaneous
chemical_list: D042501:Angiogenic Proteins; D015415:Biomarkers
keywords: Neo-angiogenesis; Phagocytosis; Proteases; Red blood cells