CCM3 is one of mutated genes responsible for the human CCM disease, a pathological condition that affects the vasculature of the central nervous system and results in stroke, seizure and cerebral hemorrhage with a high prevalence. CCM consists of dilated and multiple capillary channels formed by a single layer of endothelium, lacking all other normal vessel wall elements. Patients with inherited autosomal dominant CCM carry loss of function mutations in one of three genes: CCM1, CCM2 and CCM3. Deletion in one of the three Ccm genes in vascular EC induces CCM lesions in mice. However, it is unknown why both humans and mice with CCM3 loss exhibit more severe phenotype than those with loss of CCM1 or CCM2. Our unexpected discovery of the involvement of CCM3 in EC exocytosis, prompt us to hypothesize that alteration in CCM3-regulated EC exocytosis contributes to the pathogenesis of the CCM disease. We propose the following two specific aims: 1) To determine the role of CCM3-regulated brain EC exocytosis in CCM disease phenotypes. We will establish mouse CCM models even closer to human CCM disease by creating brain EC-specific Ccm3 deletion, and determine therapeutic effects of Angpt2 neutralization antibodies in the new CCM3 mouse models. 2) To explore crosstalk of CCM3-mediated EC exocytosis with other pathways implicated in CCM formation. We will test if inhibition of exocytosis in ECs blocks RhoA-dependent EC stress fiber formation, TGF-?/Smad/BMP-mediated EndMT signaling, and MEKK3-ERK5-KLF4-mediated matrix remodeling. Conversely, test if gain- or loss-of-function of RhoA, TGF-? and MEKK3-ERK5-KLF4 signaling regulate EC exocytosis. In summary, the complementary approaches using genetic, cell biological and imaging analyses will facilitate our understanding of the molecular mechanisms and pathogenesis involved in acquisition of cerebral cavernous malformations, and help in defining new and more effective therapies. Our findings should benefit the general understanding of the regulatory mechanisms of exocytosis, which also occurs in other cardiovascular cells and ECs of other cardiovascular organs such as heart, lung and aortae. Therefore, our present study is of broad significance in cardiovascular research.

Public Health Relevance

Cerebral cavernous malformations (CCMs) are common vascular malformations with a prevalence of 0.1-0.5% that affect the vasculature of central nervous system in the human population where they result in increased risk for stroke, seizures and focal neurological deficits. The proposed studies will use the complementary approaches of genetic, cell biological and imaging analyses to define augmented cellular secretory vesicles as the causes of CCM pathology, and define new and more effective therapies for this potentially debilitating disorder.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL136507-03
Application #
9631485
Study Section
Vascular Cell and Molecular Biology Study Section (VCMB)
Program Officer
Charette, Marc F
Project Start
2017-02-01
Project End
2021-01-31
Budget Start
2019-02-01
Budget End
2020-01-31
Support Year
3
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Yale University
Department
Pathology
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Zhou, Huanjiao Jenny; Xu, Zhe; Wang, Zongren et al. (2018) SUMOylation of VEGFR2 regulates its intracellular trafficking and pathological angiogenesis. Nat Commun 9:3303
He, Li; Pierce, Richard W; Min, Wang (2018) Rare and Low-Frequency Variant of ARHGEF17 Is Associated With Intracranial Aneurysms. Circ Genom Precis Med 11:e002248
He, Feng; Song, Zhi; Chen, Huacui et al. (2018) Long noncoding RNA PVT1-214 promotes proliferation and invasion of colorectal cancer by stabilizing Lin28 and interacting with miR-128. Oncogene :
Liu, Tingting; Zhou, Huanjiao Jenny; Min, Wang (2017) ASK family in cardiovascular biology and medicine. Adv Biol Regul 66:54-62
Tan, Shu; Feng, Boya; Yin, Mingzhu et al. (2017) Stromal Senp1 promotes mouse early folliculogenesis by regulating BMP4 expression. Cell Biosci 7:36
Zhu, Xiaolong; Ding, Sha; Qiu, Cong et al. (2017) SUMOylation Negatively Regulates Angiogenesis by Targeting Endothelial NOTCH Signaling. Circ Res 121:636-649
Chen, Chaofei; Li, Li; Zhou, Huanjiao Jenny et al. (2017) The Role of NOX4 and TRX2 in Angiogenesis and Their Potential Cross-Talk. Antioxidants (Basel) 6:
Qiu, Cong; Wang, Yuewen; Zhao, Haige et al. (2017) The critical role of SENP1-mediated GATA2 deSUMOylation in promoting endothelial activation in graft arteriosclerosis. Nat Commun 8:15426
Shao, Lan; Feng, Boya; Zhang, Yuying et al. (2016) The role of adipose-derived inflammatory cytokines in type 1 diabetes. Adipocyte 5:270-4
Jenny Zhou, Huanjiao; Qin, Lingfeng; Zhang, Haifeng et al. (2016) Endothelial exocytosis of angiopoietin-2 resulting from CCM3 deficiency contributes to cerebral cavernous malformation. Nat Med 22:1033-1042

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