Selective Endothelial Hyperactivation of Oncogenic KRAS Induces Brain Arteriovenous Malformations in Mice
Eun S. Park PhD
Vivian L. Smith Department of Neurosurgery, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX
Search for more papers by this authorSehee Kim PhD
Vivian L. Smith Department of Neurosurgery, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX
Search for more papers by this authorShuning Huang PhD
Department of Diagnostic and Interventional Imaging, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX
Search for more papers by this authorJi Young Yoo PhD
Vivian L. Smith Department of Neurosurgery, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX
Search for more papers by this authorJakob Körbelin PhD
II. Department of Internal Medicine, Center of Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
Search for more papers by this authorTae Jin Lee PhD
Vivian L. Smith Department of Neurosurgery, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX
Search for more papers by this authorBalveen Kaur PhD
Vivian L. Smith Department of Neurosurgery, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX
Search for more papers by this authorPramod K. Dash PhD
Department of Neurobiology and Anatomy, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX
Search for more papers by this authorCorresponding Author
Peng R. Chen MD
Vivian L. Smith Department of Neurosurgery, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX
Address correspondence to Peng Roc Chen or Eunhee Kim, Vivian L. Smith Department of Neurosurgery, McGovern Medical School, University of Texas Health Science Center at Houston, 6431 Fannin Street, Houston, TX 77030, USA. E-mail: [email protected], [email protected]
Search for more papers by this authorCorresponding Author
Eunhee Kim PhD
Vivian L. Smith Department of Neurosurgery, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX
Address correspondence to Peng Roc Chen or Eunhee Kim, Vivian L. Smith Department of Neurosurgery, McGovern Medical School, University of Texas Health Science Center at Houston, 6431 Fannin Street, Houston, TX 77030, USA. E-mail: [email protected], [email protected]
Search for more papers by this authorEun S. Park PhD
Vivian L. Smith Department of Neurosurgery, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX
Search for more papers by this authorSehee Kim PhD
Vivian L. Smith Department of Neurosurgery, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX
Search for more papers by this authorShuning Huang PhD
Department of Diagnostic and Interventional Imaging, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX
Search for more papers by this authorJi Young Yoo PhD
Vivian L. Smith Department of Neurosurgery, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX
Search for more papers by this authorJakob Körbelin PhD
II. Department of Internal Medicine, Center of Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
Search for more papers by this authorTae Jin Lee PhD
Vivian L. Smith Department of Neurosurgery, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX
Search for more papers by this authorBalveen Kaur PhD
Vivian L. Smith Department of Neurosurgery, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX
Search for more papers by this authorPramod K. Dash PhD
Department of Neurobiology and Anatomy, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX
Search for more papers by this authorCorresponding Author
Peng R. Chen MD
Vivian L. Smith Department of Neurosurgery, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX
Address correspondence to Peng Roc Chen or Eunhee Kim, Vivian L. Smith Department of Neurosurgery, McGovern Medical School, University of Texas Health Science Center at Houston, 6431 Fannin Street, Houston, TX 77030, USA. E-mail: [email protected], [email protected]
Search for more papers by this authorCorresponding Author
Eunhee Kim PhD
Vivian L. Smith Department of Neurosurgery, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX
Address correspondence to Peng Roc Chen or Eunhee Kim, Vivian L. Smith Department of Neurosurgery, McGovern Medical School, University of Texas Health Science Center at Houston, 6431 Fannin Street, Houston, TX 77030, USA. E-mail: [email protected], [email protected]
Search for more papers by this authorAbstract
Objective
Brain arteriovenous malformations (bAVMs) are a leading cause of hemorrhagic stroke and neurological deficits in children and young adults, however, no pharmacological intervention is available to treat these patients. Although more than 95% of bAVMs are sporadic without family history, the pathogenesis of sporadic bAVMs is largely unknown, which may account for the lack of therapeutic options. KRAS mutations are frequently observed in cancer, and a recent unprecedented finding of these mutations in human sporadic bAVMs offers a new direction in the bAVM research. Using a novel adeno-associated virus targeting brain endothelium (AAV-BR1), the current study tested if endothelial KRASG12V mutation induces sporadic bAVMs in mice.
Methods
Five-week-old mice were systemically injected with either AAV-BR1-GFP or -KRASG12V. At 8 weeks after the AAV injection, bAVM formation and characteristics were addressed by histological and molecular analyses. The effect of MEK/ERK inhibition on KRASG12V-induced bAVMs was determined by treatment of trametinib, a US Food and Drug Administration (FDA)-approved MEK/ERK inhibitor.
Results
The viral-mediated KRASG12V overexpression induced bAVMs, which were composed of a tangled nidus mirroring the distinctive morphology of human bAVMs. The bAVMs were accompanied by focal angiogenesis, intracerebral hemorrhages, altered vascular constituents, neuroinflammation, and impaired sensory/cognitive/motor functions. Finally, we confirmed that bAVM growth was inhibited by trametinib treatment.
Interpretation
Our innovative approach using AAV-BR1 confirms that KRAS mutations promote bAVM development via the MEK/ERK pathway, and provides a novel preclinical mouse model of bAVMs which will be useful to develop a therapeutic strategy for patients with bAVM. ANN NEUROL 2021;89:926–941
Potential Conflicts of Interest
Dr. Jakob Körbelin is an inventor of a patent hold by Boehringer Ingelheim concerning viral capsid peptides to direct AAVs to cerebral endothelial cells. There is nothing to report by the other authors.
Supporting Information
| Filename | Description |
|---|---|
| ana26059-sup-0001-Movies.zipapplication/x-zip-compressed, 16.7 MB | Movie S1 to S4. MR angiography displays abnormal vasculatures in KRASG12V/bEC mice. The 7 T MR angiography (MRA) displays the development of tangled vasculatures in both axial (Supplementary Movie S3) and sagittal views (Supplementary Movie S4) in KRASG12V/bEC mice compared with GFPbEC mice (Supplementary Movie S1 axial view and Supplementary Movie S2 sagittal view). |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
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