Myeloid Cell Regulation of Cerebrovascular Basal and Functional Tone - The brain is an energy demanding organ. Its high energy demands are supplied on demand by a network of blood vessels that make up the vascular tree. When disrupted, cerebrovascular deficits have detrimental consequences, which is a feature of various diseases including neurodegenerative diseases such as Alzheimer’s disease (AD). Therefore, regulation of the brain’s vasculature is under tight control and cellular mechanisms governing this are important. Brain myeloid cells include resident microglia (MG) and border associated macrophages (BAMs) and especially perivascular macrophages (PVMs) that associate with the vasculature. Myeloid cell dysfunction is a notable feature of AD, where genome wide association studies (GWAS) identify microglial-specific genes as risk genetic loci for AD. Nevertheless, distinguishing myeloid cell roles in the regulation of vascular structure and blood flow in health has been poorly explored. Our preliminary data indicate: (a) that distinct myeloid cells localize to distinct components of the vascular tree, (b) that myeloid cells are lost but only microglia repopulate by 8 days of global pharmacological elimination, (c) that capillaries exhibit structural reductions upon microglial loss and restoration upon repopulation, and (d) that microglial COX1 deletion reduces capillary size and blood flow. Based on these findings, we hypothesize that microglia at capillaries and border associated macrophages (especially perivascular macrophages) at arterioles and venules maintain basal vascular tone and facilitate vascular responses to hypercapnia through COX1. This hypothesis will be tested in two specific aims using longitudinal in vivo 2Photon (2P) imaging approaches to first distinguish microglia (MG) and perivascular macrophage (PVM) roles in maintaining basal vascular structure and blood flow in Aim 1, then ascertain COX1 roles in myeloid cell regulation of hypercapnic vascular responses in Aim 2.
