Molecular profiling of the stroke-induced alterations in the cerebral microvasculature reveals promising therapeutic candidates.

TitleMolecular profiling of the stroke-induced alterations in the cerebral microvasculature reveals promising therapeutic candidates.
Publication TypeJournal Article
Year of Publication2023
AuthorsCallegari K, Dash S, Uchida H, Shingai Y, Liu C, Khodarkovskaya A, Lee Y, Ito A, Lopez A, Zhang T, Xiang J, Kluk MJ, Sanchez T
JournalProc Natl Acad Sci U S A
Volume120
Issue16
Paginatione2205786120
Date Published2023 Apr 18
ISSN1091-6490
KeywordsAnimals, Blood-Brain Barrier, Brain, Endothelium, Humans, Mice, Microvessels, Sphingolipids, Stroke
Abstract

Stroke-induced cerebral microvascular dysfunction contributes to aggravation of neuronal injury and compromises the efficacy of current reperfusion therapies. Understanding the molecular alterations in cerebral microvessels in stroke will provide original opportunities for scientific investigation of novel therapeutic strategies. Toward this goal, using a recently optimized method which minimizes cell activation and preserves endothelial cell interactions and RNA integrity, we conducted a genome-wide transcriptomic analysis of cerebral microvessels in a mouse model of stroke and compared these transcriptomic alterations with the ones observed in human, nonfatal, brain stroke lesions. Results from these unbiased comparative analyses have revealed the common alterations in mouse stroke microvessels and human stroke lesions and identified shared molecular features associated with vascular disease (e.g., Serpine1/Plasminogen Activator Inhibitor-1, Hemoxygenase-1), endothelial activation (e.g., Angiopoietin-2), and alterations in sphingolipid metabolism and signaling (e.g., Sphigosine-1-Phosphate Receptor 2). Sphingolipid profiling of mouse cerebral microvessels validated the transcript data and revealed the enrichment of sphingomyelin and sphingoid species in the cerebral microvasculature compared to brain and the stroke-induced increase in ceramide species. In summary, our study has identified novel molecular alterations in several microvessel-enriched, translationally relevant, and druggable targets, which are potent modulators of endothelial function. Our comparative analyses have revealed the presence of molecular features associated with cerebral microvascular dysfunction in human chronic stroke lesions. The results shared here provide a detailed resource for therapeutic discovery of candidates for neurovascular protection in stroke and potentially, other pathologies exhibiting cerebral microvascular dysfunction.

DOI10.1073/pnas.2205786120
Alternate JournalProc Natl Acad Sci U S A
PubMed ID37058487
PubMed Central IDPMC10120001
Grant ListR01 HL094465 / HL / NHLBI NIH HHS / United States
R01 NS114561 / NS / NINDS NIH HHS / United States
Related Faculty: 
Michael Kluk, M.D., Ph.D. Teresa Sanchez, Ph.D.

Pathology & Laboratory Medicine 1300 York Avenue New York, NY 10065 Phone: (212) 746-6464
Surgical Pathology: (212) 746-2700