Scrib in Endothelial Cell Migration (p 924)
Polarity protein Scrib tells vascular endothelial cells which way to go, report Michaelis et al.
As new blood vessels form, endothelial cells must not only migrate into their appropriate positions, but also arrange themselves so that their apical surfaces face the vessel lumen. In other cell types, migration and orientation are controlled by factors called polarity proteins, but surprisingly few studies have examined the role of these factors in endothelial cells. Michaelis and colleagues have now discovered that silencing the polarity protein, Scrib, in cultured vascular endothelial cells disrupts cell orientation, directed migration, and vessel formation. Their immunoprecipitation studies reveal that Scrib interacts with integrin α5, a transmembrane protein responsible for binding the extracellular matrix and regulating cell migration. Scrib not only promoted the cell surface expression of integrin 5, but also prevented its lysosomal degradation. In addition, the team showed that either the knock-out of Scrib in mouse embryos or the knock-down of Scrib in zebrafish embryos caused both the delay and disruption of blood vessel development. This newly identified role in angiogenesis could make Scrib a promising target for both pro- and anti-angiogenic treatments, say the authors.
Living Without Creatine (p 945)
Contrary to popular belief, creatine may not be essential for high-energy performance, say Lygate et al.
Creatine, a molecule abundant in heart and skeletal muscle cells, is dramatically reduced in the failing heart. And because creatine converts readily to and from phosphocreatine, it is thought to be a major transporter and source of phosphate for ATP production. In addition, mice lacking creatine have stunted maximal heart muscle activity and recover poorly if at all from myocardial infarction. Such observations have led to the conclusion that even though creatine may not be necessary for basal muscle activity, it is necessary for high-energy expenditure, particularly under conditions of stress. However, Lygate and colleagues now challenge that view. They say the method for eliminating creatine in previous studies might have caused off-target effects. To address this issue, the team engineered mice that lacked an essential creatine production enzyme. Surprisingly, these mice, although 100 percent creatine-free, could run just as far and just as fast as wild type mice. They also exhibited the same capacity for exercise on a treadmill and showed equivalent recovery and survival after myocardial infarction. These findings raise the question, if creatine is not required for high energy performance, why is it present in high-energy cells? The authors suggest creatine may play, an as yet undetermined role, in longer-term energy production.
Mutation in VEGFC and Primary Lymphedema (p 956)
Gordon et al discover a novel mutation that causes Milroy disease-like primary lymphedema.
Milroy disease is an inherited condition in which congenital abnormalities in the lymphatic vessels prevent the proper drainage of tissue fluid, causing characteristic swelling in the legs and feet. Although the most common cause of Milroy disease is a mutation in the vascular endothelial growth factor receptor 3 (VEGFR3), nearly 30 percent of patients do not carry such a mutation. To search for alternative causes, Gordon and colleagues performed whole exome sequencing on five Milroy disease patients that were free of mutations in VEGFR3. One of these patients showed a mutation in a VEGFC, a ligand of VEGFR3. This mutation caused a translational frameshift that generated a truncated protein. Three members of this patient’s family also displayed Milroy-like lymphedema, while carrying the very same VEGFC mutation. Functional studies in zebrafish showed that while wild type VEGFC protein induced the sprouting of both blood and lymph vessels, the mutant truncated form of the protein did not. In light of these results, the authors suggest that patients who present with Milroy disease symptoms without a VEGFR3 mutation should be screened for mutations in VEGFC.
- © 2013 American Heart Association, Inc.