Alcocer, J. | Search bioRxiv

bioRxiv2026

A Perturb-seq screen guided by species divergence uncovers pathways for collateral artery formation

Collateral arteries are natural bypasses that can reroute blood flow around arterial blockages, limiting tissue injury during stroke and coronary artery disease. Despite their clinical effectiveness, therapeutic strategies to stimulate collateral artery growth remain unavailable due to our limited understanding of their developmental mechanisms. Remarkably, guinea pigs display exceptionally dense collateral artery networks across various organs, resulting in complete resistance to ischemic damage in the brain and heart. In this study, we compared single-cell RNA sequencing (scRNA-seq) from guinea pig and mouse tissues to identify endothelial cell (EC) gene expression patterns associated with extensive collateral artery development. We then developed an in vivo Perturb-seq platform in mice to test whether genes differentially expressed in guinea pigs influence artery EC specification. This pipeline identified artery repressors that were downregulated in guinea pigs and increased pial collateral abundance when inhibited in mice. Downstream analysis suggests that artery repressors, including WNT and hypoxia response genes, function in two capillary EC subsets--Esm1+ pre-artery and Apln+ angiogenic tip cells. Reduced activity of these repressors allows more ECs to acquire arterial identity, potentiating collateral artery formation. Collectively, our study establishes a strategy for discovering the genes underlying species-specific traits, suggests that guinea pigs have collaterals due to decreased activity of artery inhibitor pathways and hypoxia responses, and identifies novel targets for stimulating collateral artery formation (Graphical abstract). O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=174 SRC="FIGDIR/small/721711v2_ufig1.gif" ALT="Figure 1"> View larger version (52K): org.highwire.dtl.DTLVardef@18b36cdorg.highwire.dtl.DTLVardef@bafbaforg.highwire.dtl.DTLVardef@1e1a6bdorg.highwire.dtl.DTLVardef@189f585_HPS_FORMAT_FIGEXP M_FIG C_FIG

developmental biology↗

bioRxiv2019

Cerebral perfusion and metabolism coupling during a critical time window provides rapid assessment of cardiac arrest severity and prognosis in a preclinical model

Improved quantitative understanding of the dynamic relationship among cerebral blood flow, oxygen consumption, and electrical activity is important to clinicians treating acute brain injury. Such knowledge would elucidate the neurovascular response to ischemia, helping to potentially guide treatment. Using a multimodal optical imaging platform and a clinically-relevant rat model of cardiac arrest (CA) and cardiopulmonary resuscitation (CPR), we continuously measured cerebral blood flow (CBF), brain tissue oxygenation (StO2), cerebral metabolic rate of oxygen (CMRO2), and cerebral electrical activity (electrocorticography; ECoG). Multiple phases of cerebral hemodynamic recovery, with different degrees of mismatch between CBF and CMRO2, were observed following CPR. At 1 min post-resuscitation, we observed that the ratio CBF/CMRO2 is indicative of CA duration/severity and prognostic (with 87% accuracy) of short-term neurological recovery measured by the re-initiation of ECoG activity. These measurements provide the earliest known metrics for assessment of CA severity and prognosis post-CPR. Interestingly, the accuracy of this information is lost beyond 2-3 minutes post-CPR, highlighting a critical, easily overlooked, period immediately post-CPR. These metrics do not require pre-resuscitation data, underscoring translational potential in emergency-response settings when pre-CA information is unavailable. These metrics encourage validation in human studies, potentially offering real-time feedback during CA/CPR to optimize neurological outcome.

neuroscience↗