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Specialized pericyte subtypes in the pulmonary capillaries

ABSTRACT: Pericytes (PCs) are essential for capillary stability and homeostasis, with impaired PC function linked to diseases like pulmonary arterial hypertension (PAH). Investigating PC biology has been challenging due to the lack of specific markers, making it difficult to distinguish PCs from other stromal cells. Using bioinformatic analysis and RNAscope, we identified Higd1b as a unique gene marker for PCs and generated a novel knockin mouse line, Higd1b-CreERT2, that accurately labels PCs in the lung and heart. Single-cell RNA sequencing revealed two distinct Higd1b+ PC subtypes, with Type 1 PCs supporting capillary homeostasis and Type 2 PCs accumulating in arterioles, coexpressing smooth muscle markers and increased levels of Vimentin under hypoxic conditions. Lastly, healthy human lung PCs with upregulation of Vimentin exhibited increased adhesion, migration, and increased expression levels of SM22 in vitro. These findings highlight the specialization of pulmonary PCs and their contribution to vascular remodeling in hypoxia-induced pulmonary hypertension (PH), offering new insights into PC function and regulation.

SUBMITTER: Ke Yuan

PROVIDER: S-SCDT-10_1038-S44318-024-00349-1 | biostudies-other |

REPOSITORIES: biostudies-other

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Project description:An impairment of amyloid β-peptide (Aβ) clearance is suggested to play a key role in the pathogenesis of sporadic Alzheimer's disease (AD). Amyloid degradation is mediated by various mechanisms including fragmentation by enzymes like neprilysin, matrix metalloproteinases (MMPs) and a recently identified amyloidolytic activity of β-site amyloid precursor protein cleaving enzyme 1 (BACE1). BACE1 cleavage of Aβ40 and Aβ42 results in the formation of a common Aβ34 intermediate which was found elevated in cerebrospinal fluid levels of patients at the earliest disease stages. To further investigate the role of Aβ34 as a marker for amyloid clearance in AD, we performed a systematic and comprehensive analysis of Aβ34 immunoreactivity in hippocampal and cortical post-mortem brain tissue from AD patients and non-demented elderly individuals. In early Braak stages, Aβ34 was predominantly detectable in a subset of brain capillaries associated with pericytes, while in later disease stages, in clinically diagnosed AD, this pericyte-associated Aβ34 immunoreactivity was largely lost. Aβ34 was also detected in isolated human cortical microvessels associated with brain pericytes and its levels correlated with Aβ40, but not with Aβ42 levels. Moreover, a significantly decreased Aβ34/Aβ40 ratio was observed in microvessels from AD patients in comparison to non-demented controls suggesting a reduced proteolytic degradation of Aβ40 to Aβ34 in AD. In line with the hypothesis that pericytes at the neurovascular unit are major producers of Aβ34, biochemical studies in cultured human primary pericytes revealed a time and dose dependent increase of Aβ34 levels upon treatment with recombinant Aβ40 peptides while Aβ34 production was impaired when Aβ40 uptake was reduced or BACE1 activity was inhibited. Collectively, our findings indicate that Aβ34 is generated by a novel BACE1-mediated Aβ clearance pathway in pericytes of brain capillaries. As amyloid clearance is significantly reduced in AD, impairment of this pathway might be a major driver of the pathogenesis in sporadic AD.

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Specialized pericyte subtypes in the pulmonary capillaries

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