Microvascular Sprouting, Extension, and Creation of New Capillary Connections with Adaptation of the Neighboring Astrocytes in Adult Mouse Cortex under Chronic Hypoxia

Abstract

The present study aimed to determine the spatiotemporal dynamics of microvascular and astrocytic adaptation during hypoxiainduced cerebral angiogenesis. Adult C57BL/6J and Tie2-green fluorescent protein (GFP) mice with vascular endothelial cells expressing GFP were exposed to normobaric hypoxia for 3 weeks, whereas the three-dimensional microvessels and astrocytes were imaged repeatedly using two-photon microscopy. After 7 to14 days of hypoxia, a vessel sprout appeared from the capillaries with a bump-like head shape (mean diameter 14 mm), and stagnant blood cells were seen inside the sprout. However, no detectable changes in the astrocyte morphology were observed for this early phase of the hypoxia adaptation. More than 50% of the sprouts emerged from capillaries 60 mm away from the center penetrating arteries, which indicates that the capillary distant from the penetrating arteries is a favored site for sprouting. After 14 to 21 days of hypoxia, the sprouting vessels created a new connection with an existing capillary. In this phase, the shape of the new vessel and its blood flow were normalized, and the outside of the vessels were wrapped with numerous processes from the neighboring astrocytes. The findings indicate that hypoxia-induced cerebral angiogenesis provokes the adaptation of neighboring astrocytes, which may stabilize the blood-brain barrier in immature vessels.

Micro-Heterogeneity of Flow in a Mouse Model of Chronic Cerebral Hypoperfusion Revealed by Longitudinal Doppler Optical Coherence Tomography and Angiography

“…The question of whether the dropout is a consequence of exclusion of cells from plasma-only perfused paths, complete capillary collapse, or leukocyte plugging remains to be investigated using other more specific labeling approaches. 31 The potential role of factors such as edema or active pericyte constriction 32 should also be explored. Last, our data suggest that prominent changes in RBC-perfused capillary density were present mainly below a threshold flow of around 60 mL/100 g per minute ( Figure 6H).…”

Large-scale recording of astrocyte activity

“…In ischemic stroke, astrocytes at and near the lesion site show larger amplitude, higher frequency, and more synchronized, calcium wave-like activity during the acute phase [76]; changes in astrocytic calcium responses were also seen in the contralateral hemisphere [77], suggesting that their activity can be altered without direct injury. In addition, astrocytes show region-dependent structural changes during early and late post-ischemic phases [78,79]. Similarly complex structural and functional alterations are seen in other cell types [80-82].…”

Hypoxic postconditioning reduces microglial activation, astrocyte and caspase activity, and inflammatory markers after hypoxia–ischemia in the neonatal rat brain

“…This suggests that a mechanism for PostC induced neuroprotection might be by enhancing the interaction between astrocytes and the potential protection of the blood-brain barrier. A recent study showed that chronic hypoxia was able to induce the growth of blood vessels and elicit astrocyte adaptation around new blood vessels, thereby stabilizing the blood-brain barrier (30). Furthermore, reactive astrocytes were seen to reduce infarct volume after an ischemic brain injury in mice through glutamate uptake, astrocyte gap junctional communication and possibly reconstruct the compromised blood-brain barrier (7).…”