{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T14:02:53Z","timestamp":1753884173336,"version":"3.41.2"},"reference-count":35,"publisher":"The Company of Biologists","license":[{"start":{"date-parts":[[2021,5,18]],"date-time":"2021-05-18T00:00:00Z","timestamp":1621296000000},"content-version":"am","delay-in-days":868,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100000009","name":"Foundation for the National Institutes of Health","doi-asserted-by":"publisher","award":["NS076729"],"award-info":[{"award-number":["NS076729"]}],"id":[{"id":"10.13039\/100000009","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:p>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 TGF\u03b2 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 \u03b28, a limiting activator of pro-TGF\u03b2. In this study, we use mice to test if 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. To our surprise, we found that there is a narrow developmental window during which this pathway is amenable to manipulation. While 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 critical for success. These findings thus provide critical new insights into both brain neurovascular biology and the intervention of GMH.<\/jats:p>","DOI":"10.1242\/dmm.041228","type":"journal-article","created":{"date-parts":[[2019,10,10]],"date-time":"2019-10-10T17:49:36Z","timestamp":1570729776000},"source":"Crossref","is-referenced-by-count":2,"title":["Harnessing region-specific neurovascular signaling to promote germinal matrix vessel maturation and hemorrhage prevention"],"prefix":"10.1242","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5998-6351","authenticated-orcid":false,"given":"Devi","family":"Santhosh","sequence":"first","affiliation":[{"name":"Departments of Neuroscience and Neurology, University of Wisconsin-Madison, Madison, WI, 53705, USA"},{"name":"Program in Genetics and Medical Genetics, University of Wisconsin-Madison, Madison, WI, 53705, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joe","family":"Sherman","sequence":"additional","affiliation":[{"name":"Departments of Neuroscience and Neurology, University of Wisconsin-Madison, Madison, WI, 53705, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shafi","family":"Chowdhury","sequence":"additional","affiliation":[{"name":"Departments of Neuroscience and Neurology, University of Wisconsin-Madison, Madison, WI, 53705, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7997-4144","authenticated-orcid":false,"given":"Zhen","family":"Huang","sequence":"additional","affiliation":[{"name":"Departments of Neuroscience and Neurology, University of Wisconsin-Madison, Madison, WI, 53705, USA"},{"name":"Program in Genetics and Medical Genetics, University of Wisconsin-Madison, Madison, WI, 53705, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"237","published-online":{"date-parts":[[2019,1,1]]},"reference":[{"key":"2021042623050280600_DMM041228C1","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1016\/j.neuron.2009.06.014","article-title":"Remote control of neuronal activity in transgenic mice expressing evolved G protein-coupled receptors","volume":"63","author":"Alexander","year":"2009","journal-title":"Neuron"},{"key":"2021042623050280600_DMM041228C2","doi-asserted-by":"publisher","first-page":"5163","DOI":"10.1073\/pnas.0700293104","article-title":"Evolving the lock to fit the key to create a family of G protein-coupled receptors potently activated by an inert ligand","volume":"104","author":"Armbruster","year":"2007","journal-title":"Proc. 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