Harnessing region-specific neurovascular signaling to promote germinal matrix vessel maturation and hemorrhage prevention
Germinal matrix hemorrhage (GMH), affecting about 1 in 300 births, is a major perinatal disease with lifelong neurological consequences. Yet despite advances in neonatal medicine, there is no effective intervention. GMH is characterized by localized bleeding in the germinal matrix (GM), due to inher...
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The Company of Biologists
2019-11-01
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doaj-d32da617a7074e9098c2246758a9e2632020-11-25T00:32:13ZengThe Company of BiologistsDisease Models & Mechanisms1754-84031754-84112019-11-01121110.1242/dmm.041228041228Harnessing region-specific neurovascular signaling to promote germinal matrix vessel maturation and hemorrhage preventionDevi Santhosh0Joe Sherman1Shafi Chowdhury2Zhen Huang3 Departments of Neuroscience and Neurology, University of Wisconsin-Madison, Madison, WI 53705, USA Departments of Neuroscience and Neurology, University of Wisconsin-Madison, Madison, WI 53705, USA Departments of Neuroscience and Neurology, University of Wisconsin-Madison, Madison, WI 53705, USA Departments of Neuroscience and Neurology, University of Wisconsin-Madison, Madison, WI 53705, USA Germinal matrix hemorrhage (GMH), affecting about 1 in 300 births, is a major perinatal disease with lifelong neurological consequences. Yet despite advances in neonatal medicine, there is no effective intervention. GMH is characterized by localized bleeding in the germinal matrix (GM), due to inherent vessel fragility unique to this developing brain region. Studies have shown that reduced TGFβ signaling contributes to this vascular immaturity. We have previously shown that a region-specific G-protein-coupled receptor pathway in GM neural progenitor cells regulates integrin β8, a limiting activator of pro-TGFβ. In this study, we use mice to test whether this regional pathway can be harnessed for GMH intervention. We first examined the endogenous dynamics of this pathway and found that it displays specific patterns of activation. We then investigated the functional effects of altering these dynamics by chemogenetics and found that there is a narrow developmental window during which this pathway is amenable to manipulation. Although high-level activity in this time window interferes with vessel growth, moderate enhancement promotes vessel maturation without compromising growth. Furthermore, we found that enhancing the activity of this pathway in a mouse model rescues all GMH phenotypes. Altogether, these results demonstrate that enhancing neurovascular signaling through pharmacological targeting of this pathway may be a viable approach for tissue-specific GMH intervention. They also demonstrate that timing and level are likely two major factors crucial for success. These findings thus provide critical new insights into both brain neurovascular biology and the intervention of GMH.http://dmm.biologists.org/content/12/11/dmm041228germinal matrix hemorrhagemouse modeltgfβ signalingbrain neurovascular biology |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Devi Santhosh Joe Sherman Shafi Chowdhury Zhen Huang |
spellingShingle |
Devi Santhosh Joe Sherman Shafi Chowdhury Zhen Huang Harnessing region-specific neurovascular signaling to promote germinal matrix vessel maturation and hemorrhage prevention Disease Models & Mechanisms germinal matrix hemorrhage mouse model tgfβ signaling brain neurovascular biology |
author_facet |
Devi Santhosh Joe Sherman Shafi Chowdhury Zhen Huang |
author_sort |
Devi Santhosh |
title |
Harnessing region-specific neurovascular signaling to promote germinal matrix vessel maturation and hemorrhage prevention |
title_short |
Harnessing region-specific neurovascular signaling to promote germinal matrix vessel maturation and hemorrhage prevention |
title_full |
Harnessing region-specific neurovascular signaling to promote germinal matrix vessel maturation and hemorrhage prevention |
title_fullStr |
Harnessing region-specific neurovascular signaling to promote germinal matrix vessel maturation and hemorrhage prevention |
title_full_unstemmed |
Harnessing region-specific neurovascular signaling to promote germinal matrix vessel maturation and hemorrhage prevention |
title_sort |
harnessing region-specific neurovascular signaling to promote germinal matrix vessel maturation and hemorrhage prevention |
publisher |
The Company of Biologists |
series |
Disease Models & Mechanisms |
issn |
1754-8403 1754-8411 |
publishDate |
2019-11-01 |
description |
Germinal matrix hemorrhage (GMH), affecting about 1 in 300 births, is a major perinatal disease with lifelong neurological consequences. Yet despite advances in neonatal medicine, there is no effective intervention. GMH is characterized by localized bleeding in the germinal matrix (GM), due to inherent vessel fragility unique to this developing brain region. Studies have shown that reduced TGFβ signaling contributes to this vascular immaturity. We have previously shown that a region-specific G-protein-coupled receptor pathway in GM neural progenitor cells regulates integrin β8, a limiting activator of pro-TGFβ. In this study, we use mice to test whether this regional pathway can be harnessed for GMH intervention. We first examined the endogenous dynamics of this pathway and found that it displays specific patterns of activation. We then investigated the functional effects of altering these dynamics by chemogenetics and found that there is a narrow developmental window during which this pathway is amenable to manipulation. Although high-level activity in this time window interferes with vessel growth, moderate enhancement promotes vessel maturation without compromising growth. Furthermore, we found that enhancing the activity of this pathway in a mouse model rescues all GMH phenotypes. Altogether, these results demonstrate that enhancing neurovascular signaling through pharmacological targeting of this pathway may be a viable approach for tissue-specific GMH intervention. They also demonstrate that timing and level are likely two major factors crucial for success. These findings thus provide critical new insights into both brain neurovascular biology and the intervention of GMH. |
topic |
germinal matrix hemorrhage mouse model tgfβ signaling brain neurovascular biology |
url |
http://dmm.biologists.org/content/12/11/dmm041228 |
work_keys_str_mv |
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