Fan Fan, M.D., M.S., FAHA

Associate Professor
Office: G328
(601) 984-1553

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Research interests

My lab has used multidisciplinary approaches with an array of techniques to investigate how microvascular dysfunction contributes to end-organ damage, including vascular cognitive impairment, Alzheimer's disease-related dementias (ADRD), stroke, and renal disease, especially with aging, hypertension, and diabetes. Together with my mentor Dr. Richard J. Roman, we identified genetic variants of genes (Add3, CYP4A, and CYP4F) involving impaired cerebral blood flow autoregulation linked to hypertension, stroke, and Alzheimer's individuals in the Atherosclerosis Risk in Communities-Neurocognitive Study (ARIC-NCS). We have generated genetically engineered rat models modifying the expression of these genes on various hypertensive and diabetic genetic backgrounds. By measurement of autoregulation of cerebral and renal blood flow in vivo utilizing laser Doppler flowmetry and laser sparkle or transonic flow probes, and measurement of myogenic response in isolated perfused cerebral and renal arteries and arterioles in vitro, we have characterized these transgenic and KO rat models. We have generated compelling evidence demonstrating cerebral and renal microvascular dysfunction may play a causal role in the development of cognitive impairments and renal injury under aging or other pathological conditions, and genetic factors may have an additive effect in this regard.

More recently, my lab has expanded our understanding of cerebral microvascular dysfunction to the cellular levels. We are studying the contribution of changes in the actin cytoskeleton (due to genetic variants of Add3) in vascular smooth muscle, endothelial, and pericytes to the myogenic response and autoregulation in cerebral circulation. We also found that the role of Add3 mutation in the modulation of the actin cytoskeleton in podocytes plays an essential role in the development of renal disease. We have reported that aging exacerbates impairments of cerebral blood flow autoregulation and cognition in diabetic rats. We dicovered that BBB leakage and neurocognitive deficits in diabetic rats are reversed by an SGLT2i without altering blood pressure or protein excretion. We have also recently reported that mitochondrial dysfunction in VSMCs and pericytes are associated with the impaired myogenic response of cerebral arteries in diabetes and presented at an international conference that inhibition of soluble epoxide hydrolase (sEH) ameliorates cerebral vascular function and reverses cognitive impairments in elderly diabetic rats. Additionally, we found reduced pericyte and tight junction coverage in old diabetic rats are associated with hyperglycemia-induced cerebrovascular pericyte dysfunction. To date, our findings demonstrate that hyperglycemia and oxidative stress are essential factors in promoting cerebral vascular dysfunction by damaging cerebral mural cells and contributing to dementia. We found that the underlying mechanisms involve advanced glycation end products-diminished endothelia-pericyte crosstalk and that hyperglycemia and ROS diminish and redistribute the contractile unit, formed by actin and myosin, in VSMCs by downregulation of myosin light chain regulatory protein.

Selected publications

• • Zhang H, Roman RJ, Fan F. Hippocampus is More Susceptible to Hypoxic Injury: Has the Rosetta Stone of Regional Variation in Neurovascular Coupling Been Deciphered? Geroscience. 2021, 0000-0000 [In Press]
  • Gonzalez-Fernandez E, Liu Y, Auchus AP, Fan F, Roman RJ. Vascular Contributions to Cognitive Impairment and Dementia: The Emerging Role of 20-HETE. Clin. Sci. 2021 Aug 13;135(15):1929-1944. doi: 10.1042/CS20201033. PMID: 34374423
  • Shin SM, Moehring F, Itson-Zoske B, Fan F, Stucky CL, Hogan QH, Yu H. Piezo2 mechanosensitive ion channel is located to sensory neurons and non-neuronal cells in rat peripheral sensory pathway: implications in pain. Pain. 2021 Jun 17. doi: 10.1097/j.pain.0000000000002356. Epub ahead of print. PMID: 34285153
  • Fan F, Booz GW, Roman RJ. Aging diabetes, deconstructing the cerebrovascular wall. Aging (Albany NY). 2021 Apr 12. 13 (7), 9158-59. doi: 10.18632/aging.202963. Epub ahead of print. PMID: 33846281
  • Fan F, and Roman RJ. Reversal of cerebral hypoperfusion: a novel therapeutic target for the treatment of AD/ADRD? Geroscience. 2021 Mar 27. doi: 10.1007/s11357-021-00357-7. Epub ahead of print. PMID:33772733
  • Liu Y, Zhang H, Yu T, Fang X, Ryu JJ, Zheng B, Chen Z, Roman RJ, and Fan F. 20-HETE-promoted cerebral blood flow autoregulation is associated with enhanced pericyte contractility. Prostaglandins Other Lipid Mediat. 2021 Mar 19;154:106548. doi: 10.1016/j.prostaglandins.2021.106548. Epub ahead of print. PMID:33753221
  • Jiao F, Varghese K, Wang S, Liu Y, Yu H, Booz GW,  Roman RJ,  Liu R, and Fan F. Recent Insights into the Neurological and Cardio-Renal Protective Mechanisms of Paeoniflorin. J Cardiovasc Pharmacol. 2021 Apr 5. Epub ahead of print. PMID: 34001724
  • Ou Y, Clifton BA, Li J, Chen T, Huang J, Li N, Wu L, Sandlin D, Allison J, Fan F, Roman RJ, Zhou W, Pang Y, Zhu H. Traumatic brain injury induced by exposure to blast overpressure via ear canal. Neural Regen Res. Neural Regen Res. 2022 Jan;17(1):115-121. doi: 10.4103/1673-5374.314311. PMID: 34100446
  • Shekhar S, Liu Y, Wang S, Zhang H, Fang X, Zhang J, Fan L, Zheng B, Roman RJ, Wang Z, Fan F, and Booz GW. Novel mechanistic insights and potential therapeutic impact of TRPC6 in neurovascular coupling and ischemic stroke. Int. J. Mol. Sci. 2021 Feb; 22(4): 2074. PMID: 33669830 PMCID: PMC7922996
  • Fan L, Gao W, Liu Y, Jefferson, J. R., Fan F, Roman R.J. Knockout of γ-Adducin Promotes N^G-Nitro-L-Arginine-Methyl-Ester (L-NAME)-Induced Hypertensive Renal Injury. J Pharmacol Exp Ther. 2021 Jan 7;JPET-AR-2020-000408. Epub ahead of print. PMID:33414130 doi: 10.1124/jpet.120.000408
  • Zhang C, Fang X, Zhang H, Hsu HJ, Roman RJ, Fan F. Genetic Susceptibility of Hypertension Induced Kidney Disease. Physiol Rep. 2021 Jan;9(1):e14688. PMID: 33377622 PMCID: PMC7772938
  • Gao W, Liu Y, Fan L, Zheng B, Jefferson JR, Wang S, Zhang H, Fang X, Nguyen BV, Zhu T, Roman RJ, and Fan F. Role of γ-Adducin in Actin Cytoskeleton Rearrangements in Podocyte Pathophysiology. Am J Physiol Renal Physiol. 2020, Dec 14. Epub ahead of print. PMID: 33308016 DOI: 10.1152/ajprenal.00423.2020