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Possible therapeutic target for cerebral cavernous malformations – common but mysterious brain blood vessel disorder

Tens of millions of people around the world have abnormal, leak-prone sproutings of blood vessels in the brain called (CCMs). These abnormal growths can lead to seizures, strokes, hemorrhages, and other serious conditions, yet their precise molecular cause has never been determined. Now, cardiovascular scientists at the at the have studied this pathway in heart development to discover an important set of molecular signals, triggered by CCM-linked gene defects, that potentially could be targeted to treat the disorder.

CCM Mouse Heart
Immunofluorescence microscopy image of a CCM mutant mouse heart is shown. The image is stained for Klf4 (green), myocardium (red) and nuclei (blue). Loss of endocardial CCM signaling leads to an up-regulated Klf4 level.
Credit:Lili Guo


The Cerebral Cavernous Malformation Pathway Controls Cardiac Development via Regulation of Endocardial MEKK3 Signaling and KLF Expression, doi:10.1016/j.devcel.2014.12.009.

The co-lead authors on the paper, graduate student Zinan Zhou and medical student David Rawnsley PhD, performed most of the experiments in the study. The co-senior author was Xiangjian Zheng, a postdoctoral researcher in the Kahn Laboratory during much the study, who recently began his own laboratory at the Centenary Institute in Sydney, Australia.

Funding was provided by the National Heart, Lung and Blood Institute (R01HL094326 , R01HL102138, R01NS075168, T32HL007971), and the American Heart Association (11SDG7430025).

University of Pennsylvania School of Medicine