mTORC1 Inhibitor Rapamycin Inhibits Growth of Cerebral Cavernous Malformation in Adult Mice.

Background: Cerebral cavernous malformations (CCMs) are vascular malformations that frequently cause stroke. CCMs arise due to loss of function in one of the genes that encode the CCM complex, a negative regulator of MEKK3-KLF2/4 signaling in vascular endothelial cells. Gain-of-function mutations in (encoding the enzymatic subunit of the PI3K (phosphoinositide 3-kinase) pathway associated with cell growth) synergize with CCM gene loss-of-function to generate rapidly growing lesions.

Sinusoidal and lymphatic vessel growth is controlled by reciprocal VEGF-C-CDH5 inhibition.

Sinusoids are specialized, low pressure blood vessels in the liver, bone marrow, and spleen required for definitive hematopoiesis. Unlike other blood endothelial cells (ECs), sinusoidal ECs express high levels of VEGFR3. VEGFR3 and its ligand VEGF-C are known to support lymphatic growth, but their function in sinusoidal vessels is unknown.

Developmental venous anomalies are a genetic primer for cerebral cavernous malformations.

Cerebral cavernous malformations (CCM) are a neurovascular anomaly that may occur sporadically, or be inherited due to autosomal dominant mutations in , , or . Individual lesions are caused by somatic mutations which have been identified in and . However, the interactions between mutations, and their relative contributions to sporadic versus familial cases remain unclear.

Cerebral Cavernous Malformation: From Mechanism to Therapy.

Cerebral cavernous malformations are acquired vascular anomalies that constitute a common cause of central nervous system hemorrhage and stroke. The past 2 decades have seen a remarkable increase in our understanding of the pathogenesis of this vascular disease. This new knowledge spans genetic causes of sporadic and familial forms of the disease, molecular signaling changes in vascular endothelial cells that underlie the disease, unexpectedly strong environmental effects on disease pathogenesis, and drivers of disease end points such as hemorrhage.

Cerebral cavernous malformations are driven by ADAMTS5 proteolysis of versican.

Cerebral cavernous malformations (CCMs) form following loss of the CCM protein complex in brain endothelial cells due to increased endothelial MEKK3 signaling and KLF2/4 transcription factor expression, but the downstream events that drive lesion formation remain undefined. Recent studies have revealed that CCM lesions expand by incorporating neighboring wild-type endothelial cells, indicative of a cell nonautonomous mechanism. Here we find that endothelial loss of ADAMTS5 reduced CCM formation in the neonatal mouse model.

Distinct cellular roles for PDCD10 define a gut-brain axis in cerebral cavernous malformation.

Cerebral cavernous malformation (CCM) is a genetic, cerebrovascular disease. Familial CCM is caused by genetic mutations in , , or Disease onset is earlier and more severe in individuals with mutations. Recent studies have shown that lesions arise from excess mitogen-activated protein kinase kinase kinase 3 (MEKK3) signaling downstream of Toll-like receptor 4 (TLR4) stimulation by lipopolysaccharide derived from the gut microbiome.

snoRNA U17 regulates cellular cholesterol trafficking.

Cholesterol is required for the growth and viability of mammalian cells and is an obligate precursor for steroid hormone synthesis. Using a loss-of-function screen for mutants with defects in intracellular cholesterol trafficking, a Chinese hamster ovary cell mutant with haploinsufficiency of the U17 snoRNA was isolated. U17 is an H/ACA orphan snoRNA, for which a function other than ribosomal processing has not previously been identified.

Box C/D small nucleolar RNA (snoRNA) U60 regulates intracellular cholesterol trafficking.

Mobilization of plasma membrane (PM) cholesterol to the endoplasmic reticulum is essential for cellular cholesterol homeostasis. The mechanisms regulating this retrograde, intermembrane cholesterol transfer are not well understood. Because mutant cells with defects in PM to endoplasmic reticulum cholesterol trafficking can be isolated on the basis of resistance to amphotericin B, we conducted an amphotericin B loss-of-function screen in Chinese hamster ovary (CHO) cells using insertional mutagenesis to identify genes that regulate this trafficking mechanism.