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Updated: May 24, 2025
A Mouse Model of Hemorrhagic Transformation Induced by Acute Hyperglycemia Combined with Transient Focal Ischemia
Published on: November 15, 2024
Development of cerebral microhemorrhages in a mouse model of hypertension
Danny F Xie1,2, Chuo Fang3, Christian Crouzet1
1Beckman Laser Institute and Medical Clinic, University of California, Irvine, CA, USA.
Abstract:
Cerebral microhemorrhages (CMH) are the pathological substrate for MRI-demonstrable cerebral microbleeds, which are associated with cognitive impairment and stroke. Aging and hypertension are the main risk factors for CMH. In this study, we investigated the development of CMH in a mouse model of aging and hypertension. Hypertension was induced in aged (17-month-old) female and male C57BL/6J mice via angiotensin II (Ang II), a potent vasoconstrictor. We investigated the vascular origin of CMH using three-dimensional images of 1-mm thick brain sections. We examined Ang II-induced CMH formation with and without telmisartan, an Ang II type 1 receptor (AT1R) blocker. To evaluate the effect of microglia and perivascular macrophages on CMH formation, mice were treated with PLX3397, a selective colony-stimulating factor 1 receptor (CSF1R) inhibitor, to achieve microglial and macrophage depletion. Iba-1 and CD206 labeling were used to study the relative contributions of microglia and macrophages, respectively, on CMH formation. CMH quantification was performed with analysis of histological sections labeled with Prussian blue. Vessels surrounding CMH were primarily of capillary size range (< 10 μm in diameter). Ang II-infused mice exhibited elevated blood pressure (p < 0.0001) and CMH burden (p < 0.001). CMH burden was significantly correlated with mean arterial pressure in mice with and without Ang II (r = 0.52, p < 0.05). Ang II infusion significantly increased Iba-1 immunoreactivity (p < 0.0001), and CMH burden was significantly correlated with Iba-1 in mice with and without Ang II (r = 0.32, p < 0.05). Telmisartan prevented elevation of blood pressure due to Ang II infusion and blocked Ang II-induced CMH formation without affecting Iba-1 immunoreactivity. PLX3397 treatment reduced Iba-1 immunoreactivity in Ang II-infused mice (p < 0.001) and blocked Ang II-induced CMH (p < 0.0001). No significant association between CMH burden and CD206 reactivity was observed. Our findings demonstrate Ang II infusion increases CMH burden. CMH in this model appear to be capillary-derived and Ang II-induced CMH are largely mediated by blood pressure. In addition, microglial activation may represent an alternate pathway for CMH formation. These observations emphasize the continuing importance of blood pressure control and the role of microglia in hemorrhagic cerebral microvascular disease.
Insights
Hypertension induced by angiotensin II increases cerebral microhemorrhages (CMH) in aged mice, primarily from capillaries. Blood pressure control and microglial activation are key factors in this hemorrhagic cerebral microvascular disease.
Area of Science:
- Neuroscience
- Vascular Biology
- Pathology
Background:
- Cerebral microhemorrhages (CMH) are linked to cognitive decline and stroke.
- Aging and hypertension are primary risk factors for CMH.
- Understanding CMH development is crucial for preventing associated neurological conditions.
Purpose of the Study:
- To investigate the development of CMH in a mouse model of aging and hypertension.
- To explore the vascular origin of CMH.
- To determine the roles of blood pressure, angiotensin II (Ang II), telmisartan, and microglial activation in CMH formation.
Main Methods:
- Hypertension was induced in aged mice using Ang II infusion.
- Three-dimensional imaging was used to study CMH vascular origins.
- Mice were treated with telmisartan (an AT1R blocker) and PLX3397 (a CSF1R inhibitor for microglial depletion).
- CMH burden was quantified using Prussian blue staining; Iba-1 and CD206 labeling assessed microglial and macrophage contributions.
Main Results:
- Ang II infusion significantly increased blood pressure and CMH burden.
- CMH burden correlated with mean arterial pressure and Iba-1 immunoreactivity.
- Telmisartan prevented Ang II-induced hypertension and CMH.
- PLX3397 treatment reduced microglial activation and blocked Ang II-induced CMH.
- Capillary-sized vessels were primarily involved in CMH formation.
Conclusions:
- Ang II infusion increases CMH burden, primarily from capillaries, mediated significantly by blood pressure.
- Microglial activation presents an alternative pathway for CMH development.
- Maintaining blood pressure control and understanding microglial roles are vital for managing hemorrhagic cerebral microvascular disease.
