ETUDE DE L'ACTIVATION DES CELLULES ENDOTHELIALES EN TRANSPLANTATION (EXPRESSION DIFFERENTIELLE DES GENES EN REPONSE A LA FIXATION DES ANTICORPS NATURELS EXOGENIQUES (DOCTORAT IMMUNOLOGIE))

NANTES-BU Médecine pharmacie (441092101) / SudocPARIS-BIUM (751062103) / SudocPARIS-BIUP (751062107) / SudocSudocFranceF

Impaired retinoic acid signaling in cerebral cavernous malformations

International audienceThe capillary-venous pathology cerebral cavernous malormation (CCM) is caused by loss o CCM1/Krev interaction trapped protein 1 (KRIT1), CCM2/MGC4607, or CCM3/PDCD10 in some endothelial cells. Mutations o CCM genes within the brain vasculature can lead to recurrent cerebral hemorrhages. Pharmacological treatment options are urgently needed when lesions are located in deeply-seated and inoperable regions o the central nervous system. Previous pharmacological suppression screens in disease models o CCM led to the discovery that treatment with retinoic acid improved CCM phenotypes. This nding raised a need to investigate the involvement o retinoic acid in CCM and test whether it has a curative eect in preclinical mouse models. Here, we show that components o the retinoic acid synthesis and degradation pathway are transcriptionally misregulated across disease models o CCM. We complemented this analysis by pharmacologically modiying retinoic acid levels in zebrash and human endothelial cell models o CCM, and in acute and chronic mouse models o CCM. Our pharmacological intervention studies in CCM2-depleted human umbilical vein endothelial cells (HUVECs) and krit1 mutant zebrash showed positive eects when retinoic acid levels were increased. However, therapeutic approaches to prevent the development o vascular lesions in adult chronic murine models o CCM were drug regiment-sensitive, possibly due to adverse developmental eects o this hormone. A treatment with high doses o retinoic acid even worsened CCM lesions in an adult chronic murine model o CCM. This study provides evidence that retinoic acid signaling is impaired in the CCM pathophysiology and suggests that modication o retinoic acid levels can alleviate CCM phenotypes

Loss of α1β1 soluble guanylate cyclase, the major nitric oxide receptor, leads to moyamoya and achalasia

Moyamoya is a cerebrovascular condition characterized by a progressive stenosis of the terminal part of the internal carotid arteries (ICAs) and the compensatory development of abnormal "moyamoya" vessels. The pathophysiological mechanisms of this condition, which leads to ischemic and hemorrhagic stroke, remain unknown. It can occur as an isolated cerebral angiopathy (so-called moyamoya disease) or in association with various conditions (moyamoya syndromes). Here, we describe an autosomal-recessive disease leading to severe moyamoya and early-onset achalasia in three unrelated families. This syndrome is associated in all three families with homozygous mutations in GUCY1A3, which encodes the alpha 1 subunit of soluble guanylate cyclase (sGC), the major receptor for nitric oxide (NO). Platelet analysis showed a complete loss of the soluble alpha 1 beta 1 guanylate cyclase and showed an unexpected stimulatory role of sGC within platelets. The NO-sGC-cGMP pathway is a major pathway controlling vascular smooth-muscle relaxation, vascular tone, and vascular remodeling. Our data suggest that alterations of this pathway might lead to an abnormal vascular-remodeling process in sensitive vascular areas such as ICA bifurcations. These data provide treatment options for affected individuals and strongly suggest that investigation of GUCY1A3 and other members of the NO-sGC-cGMP pathway is warranted in both isolated early-onset achalasia and non-syndromic moyamoya