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Harnessing region-specific neurovascular signaling to promote germinal matrix vessel maturation and hemorrhage prevention.

ABSTRACT: 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? 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 ?8, a limiting activator of pro-TGF?. 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.

SUBMITTER: Santhosh D

PROVIDER: S-EPMC6899033 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Harnessing region-specific neurovascular signaling to promote germinal matrix vessel maturation and hemorrhage prevention.

Santhosh Devi D Sherman Joe J Chowdhury Shafi S Huang Zhen Z

Disease models & mechanisms 20191111 11

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-p ...[more]

PMID: 31601549

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Project description:Germinal matrix hemorrhage (GMH) is a serious complication in extremely preterm infants associated with neurological deficits and mortality. The purpose of the present study was to develop and characterize a grade III and IV GMH model in postnatal day 5 (P5) rats, the equivalent of preterm human brain maturation. P5 Wistar rats were exposed to unilateral GMH through intracranial injection into the striatum close to the germinal matrix with 0.1, 0.2, or 0.3 U of collagenase VII. During 10 days following GMH induction, motor functions and body weight were assessed and brain tissue collected at P16. Animals were tested for anxiety, motor coordination and motor asymmetry on P22-26 and P36-40. Using immunohistochemical staining and neuropathological scoring we found that a collagenase dose of 0.3 U induced GMH. Neuropathological assessment revealed that the brain injury in the collagenase group was characterized by dilation of the ipsilateral ventricle combined with mild to severe cellular necrosis as well as mild to moderate atrophy at the levels of striatum and subcortical white matter, and to a lesser extent, hippocampus and cortex. Within 0.5 h post-collagenase injection there was clear bleeding at the site of injury, with progressive increase in iron and infiltration of neutrophils in the first 24 h, together with focal microglia activation. By P16, blood was no longer observed, although significant gray and white matter brain infarction persisted. Astrogliosis was also detected at this time-point. Animals exposed to GMH performed worse than controls in the negative geotaxis test and also opened their eyes with latency compared to control animals. At P40, GMH rats spent more time in the center of open field box and moved at higher speed compared to the controls, and continued to show ipsilateral injury in striatum and subcortical white matter. We have established a P5 rat model of collagenase-induced GMH for the study of preterm brain injury. Our results show that P5 rat pups exposed to GMH develop moderate brain injury affecting both gray and white matter associated with delayed eye opening and abnormal motor functions. These animals develop hyperactivity and show reduced anxiety in the juvenile stage.

Project description:Objective: Delayed cerebral ischemia (DCI) is a common complication after aneurysmal subarachnoid hemorrhage (aSAH) and can lead to infarction and poor clinical outcome. The underlying mechanisms are still incompletely understood, but animal models indicate that vasoactive metabolites and inflammatory cytokines produced within the subarachnoid space may progressively impair and partially invert neurovascular coupling (NVC) in the brain. Because cerebral and retinal microvasculature are governed by comparable regulatory mechanisms and may be connected by perivascular pathways, retinal vascular changes are increasingly recognized as a potential surrogate for altered NVC in the brain. Here, we used non-invasive retinal vessel analysis (RVA) to assess microvascular function in aSAH patients at different times after the ictus. Methods: Static and dynamic RVA were performed using a Retinal Vessel Analyzer (IMEDOS Systems GmbH, Jena) in 70 aSAH patients during the early (d0-4), critical (d5-15), late (d16-23) phase, and at follow-up (f/u > 6 weeks) after the ictus. For comparison, an age-matched cohort of 42 healthy subjects was also included in the study. Vessel diameters were quantified in terms of the central retinal arterial and venous equivalent (CRAE, CRVE) and the retinal arterio-venous-ratio (AVR). Vessel responses to flicker light excitation (FLE) were quantified by recording the maximum arterial and venous dilation (MAD, MVD), the time to 30% and 100% of maximum dilation (tMAD30, tMVD30; tMAD, tMVD, resp.), and the arterial and venous area under the curve (AUCart, AUCven) during the FLE. For subgroup analyses, patients were stratified according to the development of DCI and clinical outcomes after 12 months. Results: Vessel diameter (CRAE, CRVE) was significantly smaller in aSAH patients and showed little change throughout the whole observation period (p < 0.0001 vs. control for all time periods examined). In addition, aSAH patients exhibited impaired arterial but not venous responses to FLE, as reflected in a significantly lower MAD [2.2 (1.0-3.2)% vs. 3.6 (2.6-5.6)% in control subjects, p = 0.0016] and AUCart [21.5 (9.4-35.8)%*s vs. 51.4 (32.5-69.7)%*s in control subjects, p = 0.0001] on d0-4. However, gradual recovery was observed during the first 3 weeks, with close to normal levels at follow-up, when MAD and AUCart amounted to 3.0 [2.0-5.0]% (p = 0.141 vs. control, p = 0.0321 vs. d5-15) and 44.5 [23.2-61.1]%*s (p = 0.138 vs. control, p < 0.01 vs. d0-4 & d5-15). Finally, patients with clinical deterioration (DCI) showed opposite changes in the kinetics of arterial responses during early and late phase, as reflected in a significantly lower tMAD30 on d0-4 [4.0 (3.0-6.8) s vs. 7.0 (5.0-8.0) s in patients without DCI, p = 0.022) and a significantly higher tMAD on d16-23 (24.0 (21.0-29.3) s vs. 18.0 (14.0-21.0) s in patients without DCI, p = 0.017]. Conclusion: Our findings confirm and extend previous observations that aSAH results in sustained impairments of NVC in the retina. DCI may be associated with characteristic changes in the kinetics of retinal arterial responses. However, further studies will be required to determine their clinical implications and to assess if they can be used to identify patients at risk of developing DCI. Trial Registration: ClinicalTrials.gov Identifier: NCT04094155.

Project description:BACKGROUND:Neuroinflammation plays an important role in pathogenesis of germinal matrix hemorrhage (GMH). Neurotrophin-4 (NT-4) is a member of the neurotrophin family and interacts with the tropomyosin receptor kinase B (TrkB). NT-4 has been shown to confer neuroprotective effects following cerebral ischemia. We aimed to investigate the neuroprotective function of NT-4-TrkB signaling, as well as its downstream signaling cascade phosphatidylinositol-3-kinases (PI3K)/protein kinase B (Akt)/forkhead box protein O1 (FoxO1), following GMH in neonatal rats. METHODS:GMH was induced by intraparenchymal injection of bacterial collagenase (0.3?U) in P7 rat pups. A total of 163 pups were used in this study. Recombinant human NT-4 was administered intranasally at 1?h after the collagenase injection. The selective TrkB antagonist ANA-12, selective PI3K inhibitor LY294002, and FoxO1 activating CRISPR were administered intracerebroventricularly at 24?h prior to NT-4 treatment to investigate the underlying mechanism. Short-term and long-term neurobehavioral assessments, immunofluorescence staining, Nissl's staining, and Western blot were performed. RESULTS:Expression of phosphorylated TrkB increased after GMH, reaching the peak level at day 3 after hemorrhage. TrkB receptors were observed on neurons, microglia, and astrocytes. The administration of rh-NT-4 induced phosphorylation of TrkB, expression of PI3K, and phosphorylation of Akt. Meanwhile, it decreased FoxO1 and IL-6 levels. Selective inhibition of TrkB/PI3K/Akt signaling in microglia increased the expression levels of FoxO1 and pro-inflammatory cytokines. FoxO1 activating CRISPR increased the expression of IL-6, suggesting that FoxO1 might be a potential inducer of pro-inflammatory factors. These results suggested that PI3K/Akt/FoxO1 signaling may be the downstream pathway of activation of TrkB. The rat pups treated with rh-NT-4 performed better than vehicle-treated animals in both short-term and long-term behavioral tests. CONCLUSION:These data showed that rh-NT-4 reduced the expression levels of pro-inflammatory cytokines, improved neurological function, attenuated neuroinflammation, and thereby mitigated post-hemorrhagic hydrocephalus after GMH by TrkB/PI3K/Akt/FoxO1 pathway. These results indicated that rh-NT-4 could be a promising therapeutic strategy to ameliorate neuroinflammation and hydrocephalus after GMH or other similar brain injuries.

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Harnessing region-specific neurovascular signaling to promote germinal matrix vessel maturation and hemorrhage prevention.

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Harnessing region-specific neurovascular signaling to promote germinal matrix vessel maturation and hemorrhage prevention.

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