VGLL3 Links Pericyte Hypercontractility to Perivascular Fibrosis of the Cerebral Microcirculation, a Novel Vasculopathy Leading to Distinct Long-Term Cerebral Autoregulation Dysfunction After Subarachnoid Hemorrhage
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BACKGROUND
Cerebral ischemia following subarachnoid hemorrhage (SAH) has traditionally been considered transient because functional alterations of the cerebral microcirculation are thought to be self-limiting. However, we identified a previously unrecognized vasculopathy, perivascular fibrosis of the cerebral microcirculation (PFCM), characterized by excessive type I collagen deposition after SAH. This study investigated the mechanisms underlying PFCM and its subsequent effects on cerebral hemodynamics.
METHODS
In vivo SAH was modeled in mice by autologous blood injection, whereas oxygenated hemoglobin (OxyHb) exposure was used to mimic SAH in vitro . Pericyte-deficient mice ( Pdgfrβ +/- ) and pericyte-specific vestigial-like family member 3 (VGLL3) conditional knockout mice ( Vgll3 ΔPC ) were generated. Pericyte contractility was measured by nanoindentation and traction force microscopy. Molecular mechanisms were examined using Western blotting, immunofluorescence, CUT&Tag, RNA-seq, transmission electron microscopy, and molecular docking. PFCM, impaired dilation of the cerebral microcirculation, and cerebral autoregulation were assessed by two-photon imaging, transcranial Doppler with continuous blood pressure monitoring, super-resolution ultrasound imaging, and photoacoustic imaging.
RESULTS
After SAH, mice developed long-term cerebral autoregulation dysfunction marked by impaired dilation of the cerebral microcirculation, with the abnormality being most evident within the relatively lower blood pressure range. The marked reduction in PFCM in Pdgfrβ +/- mice indicated that pericytes were the principal cellular contributors. Mechanistically, OxyHb-induced cytoskeletal remodeling in vitro increased pericyte contractility and promoted nuclear translocation of SAH-upregulated VGLL3. This was followed by increased genomic occupancy, Col1a1 transcriptional activation, and type I collagen deposition. Pericyte-specific VGLL3 knockout abolished PFCM and, consequently, significantly alleviated long-term cerebral autoregulation dysfunction.
CONCLUSIONS
Our findings identify PFCM mediated by pericytic VGLL3 as a novel vasculopathy leading to long-term cerebral autoregulation dysfunction after SAH.
Clinical Perspective
What Is New?
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PFCM is a previously unrecognized vasculopathy that is mediated by pericytic VGLL3 after SAH in mice.
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PFCM is associated with persistent cerebral autoregulation dysfunction and impaired dilation of the cerebral microcirculation, challenging the traditional concept that cerebral ischemia after SAH is only transient and self-limiting.
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Pericyte-specific VGLL3 knockout abolished PFCM and, consequently, significantly attenuated long-term cerebral autoregulation dysfunction after SAH.
What Are the Clinical Implications?
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Suppressing pericyte hypercontractility reduced early cerebral ischemia and was accompanied by less PFCM and reduced persistent cerebral autoregulation dysfunction after SAH.
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Pericytic VGLL3 lies within the hypercontractility-PFCM pathway and may therefore represent a specific therapeutic target for hemodynamic impairment after SAH.
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The findings suggest that cerebral ischemia after SAH may be aggravated by hypovolemia or hypotension. This observation supports careful cardiovascular management and further evaluation of integrated heart-brain treatment strategies
