Unraveling the Role of EphA4 in Immune-Mediated Arteriogenesis After Ischemic Stroke

Simple item page
dc.contributor.authorJu, Jingen
dc.contributor.committeechairTheus, Michelle Hedricken
dc.contributor.committeememberLi, Liwuen
dc.contributor.committeememberHuckle, William Ruperten
dc.contributor.committeememberHe, Jia-Qiangen
dc.contributor.departmentBiomedical and Veterinary Sciencesen
dc.date.accessioned2024-12-20T09:01:37Zen
dc.date.available2024-12-20T09:01:37Zen
dc.date.issued2024-12-19en
dc.description.abstractStroke, a life-threatening condition, primarily resulting from ischemic events often caused by occlusion of the middle cerebral artery (MCA). Pre-existing leptomeningeal collateral (LMC) vessels connect MCA branches to anterior or posterior arteries, situated along the brain's cortical surface or meninges, under healthy conditions these vessels remain dormant due to their small diameters and relatively low flow velocity. LMCs serve as vascular redundancies that retrogradely re-supply blood to help salvage the penumbra following cerebral vascular occlusion. Their outward growth or remodeling (arteriogenesis) is essential for promoting cerebral reperfusion and preventing tissue damage after ischemic stroke. Increased fluid shear stress on collateral vessel wall activates arteriogenesis result in the activation of the endothelium and subsequent recruitment of peripheral-derived immune cells (PDICs), which have been shown to aid this unique adaptive process in other organ systems, however their role and mechanism(s) involved in LMC remodeling in stroke has not previously been evaluated. Initial findings suggest the EphA4, a well-established axonal growth and guidance receptors, plays a novel role in LMC arteriogenesis. This dissertation examined PDIC-specific functions of EphA4 using GFP labeled bone marrow chimeric mice subjected to permanent middle cerebral artery occlusion (pMCAO). We assessed immune cell population changes, infarct volume, functional recovery, characterized subtypes of infiltrated immune cell, and measured collateral vessel diameters. Additionally, we explored the Tie2-mediated PI3K signaling pathway in peripheral-derived monocyte/macrophages (PDM) treated with soluble Tie2-Fc and a PI3K p110α inhibitor. The results from this dissertation show that loss of PDIC-specific EphA4 led to increased collateral remodeling, associated with decreased infarct volume, improved cerebral blood flow, and functional recovery within 24 hours post-pMCAO. The crosstalk between EphA4-Tie2 signaling in PDMs, regulated through PI3K/Akt axis, inhibited pial collateral remodeling. In conclusion, our findings highlight the negative regulatory role of PDM-specific EphA4 in collateral growth and remodeling by inhibiting Tie2 function via the PI3K regulated pathway. Peripheral myeloid-derived EphA4 emerges as a new regulator of cerebral vascular injury and neuroinflammation following acute ischemic stroke.en
dc.description.abstractgeneralStroke, a life-threatening condition, occurs when blood flow to part of the brain is disrupted due to the vascular occlusion of a major brain artery, such as the MCA. Within protective layers of our brain, there are pre-existing pial collateral vessels that act as backup connections. These vessels play an important role in increasing cerebral reperfusion and preventing tissue damage after stroke. One fascinating aspect of stroke recovery involves PDICs. These immune cells migrate into the blood hypo-perfused region of the brain and regulate the growth of collateral vessels. However, the specific functions of PDICs, particularly a receptor called EphA4, has remained unclear. Our research delved into the immune response following ischemic stroke using genetically modified mice. We examined immune cell populations, infarct volume (the damaged brain tissue), functional recovery, and collateral vessel diameters. Notably, we discovered that deletion of PDIC-specific EphA4 enhanced collateral vessel remodeling. This led to decreased infarct volume, better blood flow, and improved functional recovery within 24 hours after stroke. Furthermore, we explored a signaling pathway involving Tie2 and PI3K in PDM. This crosstalk between EphA4 and Tie2, mediated through PI3K regulation, played a critical role in suppressing collateral vessel remodeling. In summary, understanding how immune cells contribute to stroke recovery may pave the way for novel therapeutic approaches to enhance outcomes for stroke patients.en
dc.description.degreeDoctor of Philosophyen
dc.format.mediumETDen
dc.identifier.othervt_gsexam:41473en
dc.identifier.urihttps://hdl.handle.net/10919/123857en
dc.language.isoenen
dc.publisherVirginia Techen
dc.rightsIn Copyrighten
dc.rights.urihttp://rightsstatements.org/vocab/InC/1.0/en
dc.subjectischemic strokeen
dc.subjectcollateral vesselen
dc.subjectarteriogenesisen
dc.subjectperipheral derived immune cellsen
dc.subjectmonocyte/macrophageen
dc.subjectEphA4en
dc.subjectTie2en
dc.titleUnraveling the Role of EphA4 in Immune-Mediated Arteriogenesis After Ischemic Strokeen
dc.typeDissertationen
thesis.degree.disciplineBiomedical and Veterinary Sciencesen
thesis.degree.grantorVirginia Polytechnic Institute and State Universityen
thesis.degree.leveldoctoralen
thesis.degree.nameDoctor of Philosophyen

Files

Original bundle
Now showing 1 - 1 of 1
Name:
Ju_J_D_2024.pdf
Size:
3.25 MB
Format:
Adobe Portable Document Format
Download

Collections

Doctoral Dissertations