David W. Busija, Phd

Contributions to Science

Since receiving my PhD, I have published over 300 papers primarily on the physiology of the cerebral. My major contributions are in many different areas, five of which are detailed below. In each area, I have summarized my studies and placed them into context by writing review articles. I was able to be successful in these areas due to interactions with excellent collaborators, with whom I share credit for our contributions to the advancement of science. Furthermore, I have trained many students, postdoctoral fellows, and visiting scientists in the area of the cerebral vasculature and they have done well.

1. Development of the cerebral circulation field. I was fortunate to have been present during the early days of development of studies on the cerebral circulation in which very little was known concerning regulatory mechanisms, and new approaches and methods were being developed. Since the field was wide open at the time, our studies were novel and broke new ground. Furthermore, together with colleagues, we were among the first investigators to extend studies of the cerebral circulation to the neonate in addition to adult animals. Finally, I have sustained my productivity in this field for almost 40 years and continue to receive invitations to speak during symposia and departmental seminars as well as to write comprehensive review articles.

a. Busija DW, Heistad DD. Factors involved in physiological regulation of cerebral blood flow. Rev
Physiol Pharmacol Biochem 101:161-211,1984. PMID:6441228
b. Busija DW, Bari F, Domoki F, Louis T. Mechanisms involved in the cerebrovascular dilator effects of Nmethyl-
D-aspartate in cerebral cortex. Brain Res Rev 56:89-100, 2007. PMCID: PMC2174154
c. Busija DW, Bari F, Domoki, Horiguchi T, Shimizu K. Mechanisms Involved in the Cerebrovascular
Dilator Effects of Cortical Spreading Depression. Prog Neurobiol 86:417-433, 2008. PMCID:
PMC2615412
d. Busija DW, Katakam, PV. Mitochondrial mechanisms in cerebral vascular control: Shared signaling
pathways with preconditioning. J Vasc Res 51:175-189, 2014. PMCID: PMC4149841

2. Establishing an important role of eicosanoids in cerebral vascular control. Together with collaborators such as Dr. Charles Leffler at the University of Tennessee – Memphis, I was able to establish for the first time an important role — especially in the neonate — for eicosanoids, including prostaglandins, leukotrienes, and other metabolites of arachidonic acid, in regulation of the cerebral circulation during health and injury.

a. Busija DW. Role of prostaglandins in modulating sympathetic vasoconstriction in the cerebral
circulation in anesthetized rabbits. J Cereb Blood Flow Metab 5:17-25, 1985. PMID:3972919
b. Busija DW, Leffler CW. Leukotrienes increase levels of prostanoids in cerebrospinal fluid in piglets.
Prostaglandins 32:803-812,1986. PMID:3562866
c. Busija DW, Leffler CW. Role of prostanoids in cerebrovascular responses during seizures in piglets.
Am J Physiol 256:H120-H125,1989. PMID:2912174
d. Busija DW. Eicosanoids and cerebrovascular control. In: Welch KMA, Caplan LR, Reis DJ, Siesjö BK,
Weir B, ed. Primer on Cerebrovascular Diseases. Academic Press, pp.93-96, 1997.

3. Elucidating mechanisms of protection of the brain. My laboratory was the first to demonstrate that selective targeting of mitochondria could protect the brain against anoxic/ischemic injury. In these pioneering studies, we first defined the consequences to the brain parenchyma and cerebral vasculature of ischemic injury and then developed novel approaches to prevent or remediate injury both in vivo and in cultured neurons, astroglia and endothelium.

a. Busija DW, Meng W, Bari F, McGough PS, Errico RA, Tobin JR, Louis TM. Effects of ischemia on
cerebrovascular responses to N-methyl-D-aspartate in piglets. Am J Physiol 270:H1225-H1230,1996.
PMID: 8967360
b. Mayanagi K, Gaspar T, Katakam PV, Kis B, Busija DW. The mitochondrial K(ATP) channel opener
BMS- 191095 reduces neuronal damage after transient focal cerebral ischemia in rats. J Cereb Blood
Flow Metab 27:348-55, 2007. PMID:16736040
c. Gaspar T, Snipes JA, Busija AR, Kis B, Domoki F, Bari F, Busija DW. ROS-independent
preconditioning in neurons via activation of mitoKATP channels by BMS-191095. J Cereb Blood Flow
Metab 28:1090-1103, 2008. PMID:18212794
d. Dutta S, Rutkai I, Katakam PVG, Busija DW. The mechanistic target of rapamycin (mTOR) pathway and
S6 Kinase mediate diazoxide preconditioning in primary rat cortical neurons. J Neurochem 134:845-56,
2015. PMID:26016889

4. Defining and preventing adverse effects of insulin resistance on the cerebral vasculature. Insulin resistance is an early stage in the development of the metabolic syndrome and previously was considered to be a “quiet” phase of the disease. In our studies, we showed for the first time in a comprehensive manner the adverse consequences of insulin resistance on the cerebral, mesenteric, and coronary arteries and developed new approaches for treatment and alleviation.

a. Busija DW, Miller AW, Katakam P, Erdos B. Adverse effects of reactive oxygen species on vascular
reactivity in insulin resistance. Antioxidants & Redox Signaling 8:131-1140, 2006. PMID:16910761
b. Katakam PV, Snipes JA, Steed MM, Busija DW. Insulin-induced generation of reactive oxygen species
and uncoupling of nitric oxide synthase underlie the cerebrovascular insulin resistance in obese rats. J
CerebBlood Flow Metab 32:792-804, 2012. PMID:22234336. PMCID: PMC3345912
c. Katakam PVG, Gordon A, Sure VNLR, Rutkai I, Busija DW. Diversity of mitochondrial-dependent dilator
mechanisms in vascular smooth muscle of cerebral arteries from normal and insulin resistant rats. Am J
Physiol 307:H493-503, 2014. PMCID: PMC4867394
d. Merdzo I, Rutkai I, Tokes T, Sure VN, Katakam PV, Busija DW. The mitochondrial function of the
cerebral vasculature in insulin-resistant Zucker obese rats. Am J Physiol 310:H830-838, 2016. PMCID:
PMC4867359

5. Establishing an important role of mitochondria in cerebral vascular control. My laboratory was among the first to show that mitochondrial mechanisms are important in the regulation of the cerebral circulation under normal conditions. Furthermore, we were able to show that mitochondrial influences from diverse cell types of the neurovascular unit, including neurons, endothelium, and vascular smooth muscle, are able to contribute to an integrated vascular response. We believe that mitochondrial influences are the elusive link coupling brain metabolism to blood flow. Lastly, we were the first laboratory to show that disease states such as insulin resistance and experimental strokes have complex effects on mitochondrial-derived vascular responses.

a. Busija DW, Rutkai I, Dutta S, Katakam PV. Role of mitochondria in cerebral vascular function:
Energy production, cellular protection, and regulation of vascular tone. Comprehensive Physiology,
6:1529-1548, 2016. PMID:27347901
b. Rutkai I, Merdzo I, Wunnava S, Curtin G, Katakam PVG, Busija DW. Cerebrovascular function and
mitochondrial bioenergetics after ischemia-reperfusion in male rats. J Cereb Blood Flow Metab,
39:1056- 1068, 2019. PMCID: PMC6547195
c. Cikic S, Chandra PK, Harman JC, Rutkai I, Katakam PVG, Guidry JJ, Giday JM, Busija DW. Sexual
differences in mitochondrial and related proteins in rat cerebral microvessels: A proteomic approach. J
Cereb Blood Flow Metab, 41(2):397-412, 2021. PMCID: PMC8370005
d. Rutkai I, Evan WR, Bess N, Slater-Cid T, Cikic S, Chandra PK, Katakam PVG, Mostany R, Busija DW.
Chronic imaging of mitochondria in the murine cerebral vasculature using in vivo two-photon
microscopy. Am J Physiol, 318:H1379-1386, 2020. PMCID: PMC7311694

Complete List of Published Work in MyBibliography:
https://www.ncbi.nlm.nih.gov/sites/myncbi/david.busija.1/bibliography/40721466/public/?sort=date&direction=a
scending