title: Oxidative stress and inflammation in cerebral cavernous malformation disease pathogenesis: Two sides of the same coin.
abstract: Cerebral Cavernous Malformation (CCM) is a vascular disease of proven genetic origin, which may arise sporadically or is inherited as an autosomal dominant condition with incomplete penetrance and highly variable expressivity. CCM lesions exhibit a range of different phenotypes, including wide inter-individual differences in lesion number, size, and susceptibility to intracerebral hemorrhage (ICH). Lesions may remain asymptomatic or result in pathological conditions of various type and severity at any age, with symptoms ranging from recurrent headaches to severe neurological deficits, seizures, and stroke. To date there are no direct therapeutic approaches for CCM disease besides the surgical removal of accessible lesions. Novel pharmacological strategies are particularly needed to limit disease progression and severity and prevent de novo formation of CCM lesions in susceptible individuals. Useful insights into innovative approaches for CCM disease prevention and treatment are emerging from a growing understanding of the biological functions of the three known CCM proteins, CCM1/KRIT1, CCM2 and CCM3/PDCD10. In particular, accumulating evidence indicates that these proteins play major roles in distinct signaling pathways, including those involved in cellular responses to oxidative stress, inflammation and angiogenesis, pointing to pathophysiological mechanisms whereby the function of CCM proteins may be relevant in preventing vascular dysfunctions triggered by these events. Indeed, emerging findings demonstrate that the pleiotropic roles of CCM proteins reflect their critical capacity to modulate the fine-tuned crosstalk between redox signaling and autophagy that govern cell homeostasis and stress responses, providing a novel mechanistic scenario that reconciles both the multiple signaling pathways linked to CCM proteins and the distinct therapeutic approaches proposed so far. In addition, recent studies in CCM patient cohorts suggest that genetic susceptibility factors related to differences in vascular sensitivity to oxidative stress and inflammation contribute to inter-individual differences in CCM disease susceptibility and severity. This review discusses recent progress into the understanding of the molecular basis and mechanisms of CCM disease pathogenesis, with specific emphasis on the potential contribution of altered cell responses to oxidative stress and inflammatory events occurring locally in the microvascular environment, and consequent implications for the development of novel, safe, and effective preventive and therapeutic strategies.
authors.affiliation: Department of Clinical and Biological Sciences, School of Medicine and Surgery, University of Torino, Regione Gonzole 10, 10043 Orbassano, Torino, Italy; CCM Italia Research Network(1). Electronic address: francesco.retta@unito.it.
authors.forename: Saverio Francesco
authors.initials: SF
authors.lastname: Retta
authors.affiliation: University of Rochester Medical Center, School of Medicine and Dentistry, 601 Elmwood Ave, 14642 Rochester, NY, USA. Electronic address: Angela_Glading@urmc.rochester.edu.
authors.forename: Angela J
authors.initials: AJ
authors.lastname: Glading
mesh_terms: D020786:Hemangioma, Cavernous, Central Nervous System / Q000503:physiopathology*; D006801:Humans; D007249:Inflammation; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000503:physiopathology; D018384:Oxidative Stress
keywords: Angiogenesis; Antioxidant response; Autophagy; Blood-brain barrier dysfunction; CCM1/KRIT1; CCM2; CCM3/PDCD10; Cerebral cavernous malformation (CCM); Cerebrovascular disease; Inflammation; Oxidative stress; Redox signaling; Vascular homeostasis; Vascular permeability