Novel Murine Models of Cerebral Cavernous Malformations

Abstract

Cerebral cavernous malformations (CCMs) are ectatic capillary-venous malformations that develop in approximately 0.5% of the population. Patients with CCMs may develop headaches, focal neurologic deficits, seizures, and hemorrhages. While symptomatic CCMs, depending upon the anatomic location, can be surgically removed, there is currently no pharmaceutical therapy to treat CCMs. Several mouse models have been developed to better understand CCM pathogenesis and test therapeutics. The most common mouse models induce a large CCM burden that is anatomically restricted to the cerebellum and contributes to lethality in the early days of life. These inducible models thus have a relatively short period for drug administration. We developed an inducible CCM3 mouse model that develops CCMs after weaning and provides a longer period for potential therapeutic intervention. Using this new model, three recently proposed CCM therapies, fasudil, tempol, vitamin D 3 , and a combination of the three drugs, failed to substantially reduce CCM formation when treatment was administered for 5 weeks, from postnatal day 21 (P21) to P56. We next restricted Ccm3 deletion to the brain vasculature and provided greater time (121 days) for CCMs to develop chronic hemorrhage, recapitulating the human lesions. We also developed the first model of acute CCM hemorrhage by injecting mice harboring CCMs with lipopolysaccharide. These efficient models will enable future drug studies to more precisely target clinically relevant features of CCM disease: CCM formation, chronic hemorrhage, and acute hemorrhage.

Astrocytes propel neurovascular dysfunction during cerebral cavernous malformation lesion formation

“…Recent studies have emphasized that chronic models may be more reflective of the course of the human disease (17,(55)(56)(57). We therefore, investigated the expression of VEGF increased in perilesional astrocytes in juvenile Pdcd10 ECKO ;Vegfa tm1.1Nagy mice.…”

Coronary microvascular injury in myocardial infarction: perception and knowledge for mitochondrial quality control

“…For example, damaged ECs produce TXA2, which turns on platelet activation, adhesion and aggregation onto the vascular walls 59 . Activated ECs express ADAM-15, a transmembrane cell-surface protein and member of the ADAM (a disintegrin and metalloproteinase) family, prior to its binding and activation of platelets through the GIIb/IIIa receptor in the face of MI 60 . Taken together, endothelium damage-mediated platelet activation followed by coronary artery thrombosis are the major perceived pathogenic mechanisms underscoring MI.…”

Non cell-autonomous effect of astrocytes on cerebral cavernous malformations

“…We therefore propose that astrocytes contribute to CCM disease by a non-cell-autonomous mechanism mediated by CCM endothelium-driven hypoxia and angiogenic programs.Our in vivo observations in the neonatal CCM animal model, using endothelial-specific inactivation of Pdcd10 or Krit1, revealed that lesion development is spatially restricted to zones of fibrous astrocytes, which are prevalent in the white matter of the CNS(46), and that the selective ablation of proliferative astrocytes(48) markedly reduced CCM lesion and an increase in VEGF expression, prompting the suggestion that a subset of proliferative astrocytes supports CCM lesions in the developing hindbrain. Moreover, our observations in the chronic CCM animal model(53,54), using brain endothelial-specific inactivation of Pdcd10(64), further revealed the high propensity of CCM lesions to develop surrounded by GFAP+ astrocytes throughout the CNS, including the cerebellum, cerebrum, and spinal cord. Earlier reports have shown that loss of Pdcd10 in neuroglia cells leads to formation of CCM lesions through non-cellautonomous mechanisms, implicating a role of neural cells in the CCM pathogenesis(17).…”

“…The previous studies showed increased VEGF expression in an acute neonatal CCM model. Recent studies have emphasized that chronic models may be more reflective of the course of the human disease(52–54). We therefore, investigated the expression of VEGF increased in perilesional astrocytes in juvenile Pdcd10 ECKO ;Vegfa tm1.1Nagy mice.…”