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
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…
Subarachnoid hemorrhage (SAH) often causes ischemia in the brain, which is typically considered a transient issue due to its self-limiting nature. However, researchers have now identified a new vasculopathy called perivascular fibrosis of the cerebral microcirculation (PFCM), which involves excessive deposition of type I collagen after SAH.
This study delved into the mechanisms behind PFCM and its impact on cerebral hemodynamics. Mice were used to model SAH in two ways: with autologous blood injection in vivo and oxygenated hemoglobin in vitro. To better understand the role of pericytes, researchers created two groups of mice: one with deficient pericytes (Pdgfrβ+/-) and another with pericyte-specific VGLL3 knockout (Vgll3ΔPC).
They measured pericyte contractility using nanoindentation and traction force microscopy, and studied molecular mechanisms through various techniques such as Western blotting, immunofluorescence, CUT&Tag, RNA-seq, transmission electron microscopy, and molecular docking. The results showed that after SAH, mice experienced long-term dysfunction in cerebral autoregulation, characterized by impaired dilation of the cerebral microcirculation, particularly in the lower blood pressure range.
The extent of PFCM was significantly reduced in mice lacking pericytes, indicating pericytes as the primary contributors. Mechanistically, oxygenated hemoglobin-induced cytoskeletal remodeling in vitro led to increased pericyte contractility and nuclear translocation of a protein called VGLL3, which was upregulated by SAH. This resulted in increased genomic occupancy, transcriptional activation of Col1a1, and deposition of type I collagen.
By selectively knocking out VGLL3 in pericytes, researchers found that this abolished PFCM and significantly improved long-term cerebral autoregulation dysfunction. Overall, these findings pinpoint PFCM driven by pericytic VGLL3 as a novel vasculopathy responsible for long-term cerebral autoregulation dysfunction following SAH.
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