MARILYN J. CIPOLLA

Professor
Neurology, Obstetrics, Gynecology & Reproductive Sciences , and Pharmacology

M.S., University of Vermont, 1994
Ph.D., University of Vermont, 1997

Marilyn.Cipolla@uvm.edu

Vascular cast of cerebral circulation

The arteries and arterioles that supply blood to the brain are highly specialized and include both vascular smooth muscle and endothelial cells that are unlike vascular cells from the peripheral circulation or other vascular beds. For example, the vascular smooth muscle is highly responsive to changes in pressure, a process called myogenic activity, that contributes to autoregulation of cerebral blood flow. The endothelial cells in the brain circulation are also highly specialized and provide a barrier to fluid movement called the blood-brain barrier. When these normal cell processes fail or are altered, as during disease states such as stroke and acute hypertension, significant brain damage occurs, including infarction of brain tissue and cerebral edema formation. Research in the Cipolla lab is focused at understanding the function of the cerebral circulation under normal conditions and during pathologic states. The ultimate goal is to identify therapeutic targets and decrease brain injury.

Human cerebral circulation

Because ~30% of stroke patients are hyperglycemic upon admission to the hospital, we are also interested in how high glucose levels influence the mechanisms of damage to the cerebral arterioles. Hyperglycemic stroke is known to be associated with enhanced brain damage, including a significantly higher incidence of infarction and cerebral edema formation. We are therefore studying the underlying mechanisms by which elevated glucose causes enhanced vascular dysfunction, including altered signaling pathways (e.g. protein kinase C) and second messenger production (e.g.., calcium).

Brain parenchymal arteriole mounted on glass cannulas within an arteriograph chamber and pressurized.  The video microscopy system is used to continuously measures changes in lumen diameter. Cerebral arteries and parenchymal arterioles are dissected and studied in vitro in a specialized arteriograph chamber that allows control of intravascular pressure and measurement of lumen diameter.  In this way, we can determine alterations in contractile properties that affect the extent of reperfusion and stroke outcome.

Hypertension in pregnancy and its effects on the cerebral circulation     Cannulated and pressurized artery perfused with fluorescent dextran Eclampsia is a serious complication of pregnancy that occurs when hypertension in pregnancy develops with neurologic complications, including headaches, visual disturbances, nausea, and convulsions.  While numerous organs are affected by hypertension in pregnancy, cerebrovascular involvement is the direct cause of death in approximately 40% of patients.  The major cerebrovascular changes that occur have been shown to be similar to hypertensive encephalopathy in which an acute elevation in blood pressure overcomes the myogenic vasoconstriction of the cerebral arteries and arterioles causing autoregulatory failure, hyperperfusion and edema formation.  We are interested in how both normal pregnancy and hypertension in pregnancy affects the cerebral circulation.  We are studying how these states alters diameter regulation in response to pressure (myogenic activity) as well as enhance vascular permeability in ways that affect cerebral hemodynamics and edema formation. We use a combination of in vivo models and approaches (acute hypertension, autoregulation of CBF, microspheres, in situ brain perfusion) and in vitro assays (isolated and pressurized vessels, confocal microscopy, PCR) to assess these functions.  A photo of a cannulated artery perfused with fluorescent dextran is shown to the right. This is one method of assessing blood-brain barrier permeability.
The graph on the right shows CBF autoregulatory curves in nonpregnant and late-pregnant rats. Notice that autoregulation was intact (little change in flow during increase pressure) until ~180 mm Hg when autoregulatory breakthrough occurred causing a large steep increase in flow. The graph on the right shows the resulting cerebral edema formation in response to autoregulatory breakthrough. Notice that only late-pregnant animals developed significant edema. These data suggest that normal pregnancy predisposes the brain to edema when blood pressure is acutely elevated as in eclampsia. We are interested in how pregnancy affects the cerebral circulation to promote edema, including changes in hemodynamics and blood-brain barrier properties.
		Cerebral blood flow autoregulatory curves from nonpregnant and late-pregnant rats
		Cerebral edema formation during acute hypertension in nonpregnant and late-pregnant rats From Euser and Cipolla, Hypertension 2007

Funding

Howard Hughes Medical Institute

National Institute of Neurologic Disorders and Stroke (RO1 NS043316 and RO1 NS45940)

Totman Medical Research Trust

AHA National Established Investigator Award

Honors

President's Achievement Award - Society for Gynecologic Investigation (2010)

President, Perinatal Research Society (2009)

Lang-Pardi Italy Foundation President's Presenter's Award, Society for Gynecologic Investigation (2009)

James A. Shannon Director's Award, NIH, Office of the Director

Established Investigator of the AHA

Fellow, AHA Council for High Blood Pressure Research

Fellow, Cardiovascular Section of the American Physiologic Society

Co-Chair, Stroke Progress Review Group, NINDS

Editorial Boards:

• Stroke
• Journal of Cerebral Blood Flow and Metabolism
• Journal of Cardiovascular Pharmacology and Therapeutics

Cipolla Lab Student Honors and Awards

President’s Presenters Award, Society for Gynecologic Investigation

• Anna Euser, PhD, 2006
• Marjon Wiegman, 2008

Joseph B. Warshaw Scholarship Award - Anna Euser, PhD

Predoctoral Fellowship Award, American Heart Association - Anna Euser, PhD

Cipolla Lab

Left to Right: Kelvin Siu-Lung Chan, Marilyn Cipolla, Abbie Chapman and Julie Godfrey.

Technicians - the ones who keep everything going!

Abbie Chapman	Julie Godfrey

Postdoctoral Associates

Kelvin Siu-Lung Chan

Medical Fellows

Laurie Amburgey

Lab Alumni

Annet Aukes	Ryan Crete	Anna Euser	Nicole Hoyniak
Matthew Maneen	Tim Roberts	Saman Vinke	Marjon Wiegman

 

Amburgey OA, Reeves SA, Bernstein IM and Cipolla MJ (2009). Resistance artery adaptation to pregnancy counteracts the vasoconstricting influence of plasma from normal pregnant women. Reprod Sci 2009 Sep 18. [Epub ahead of print]

Cipolla MJ, Godfrey JA, and Wiegman MJ (2009). The effect of ovariectomy and estrogen on penetrating brain arterioles and blood-brain barrier permeability. Microcirculation 2009 Aug 9:1-10. [Epub ahead of print].

Cipolla MJ, Smith J, Kohlmeyer MM, Godfrey JA (2009). SK_Ca and IK_Ca channels, myogenic tone and vasodilator responses in middle cerebral arteries and parenchymal arterioles: Effect of ischemia and reperfusion. Stroke 40:1451-1457.

Euser AG and Cipolla MJ (2009). Magnesium sulfate for treatment of eclampsia: A brief review. Stroke 40:1169-1175.

Roberts TJ, Chapman AC, and Cipolla MJ (2009). PPAR-gamma agonist rosiglitazone reverses increased cerebral venous hydraulic conductivity during hypertension. Am J Physiol 297(4):H1347-53.

Aukes AM, Bishop N, Godfrey JA and Cipolla MJ (2008). The influence of pregnancy and gender on perivascular innervartion of rat posterior cerebral arteries.  Reprod Sci 15(4):411-419.

Bernstein I and Cipolla MJ (2008). Hemodynamic contributions to the pathogenesis of preeclampsia and eclampsia: An alternative hypothesis. Fetal and Maternal Med Rev 19(1):85-104.

Cipolla, MJ and Bullinger, LV (2008). Reactivity of brain parenchymal arterioles after ischemia and reperfusion. Microcirculation, 15(6):495-501.

Cipolla MJ, Smith J, Bishop N, Bullinger LV and Godfrey J (2008). Pregnancy reverses hypertensive remodeling of cerebral arteries. Hypertension 51:1052-7.

Euser AG, Bullinger LV and Cipolla MJ (2008). Magnesium sulfate decreases blood-brain barrier permeability during acute hypertension in pregnant rats. Exp Physiol 93:254-261.

Wiegman MJ, Bullinger LV, Kohlmeyer MM, Hunter TC, and Cipolla MJ (2008). Regional expression of aquaporin-1, -4, and -9 in the brain during pregnancy. Reprod Sci 15(5):506-16.

Aukes AM, Vitullo L, Zeeman GG and Cipolla M (2007). Pregnancy prevents hypertensive remodeling and decreases myogenic reactivity in posterior cerebral arteries from Dahl salt-sensitive rats: a role in eclampsia? Am J Physiol 292:H1071-6.

Cipolla MJ (2007). Brief Review: Cerebrovascular function in pregnancy and eclampsia. Hypertension 50:14-24.

Euser AG and Cipolla MJ (2007). Cerebral blood flow autoregulation and edema formation during pregnancy in anesthetized rats. Hypertension 49:334-40.

Maneen M and Cipolla MJ (2007). Peroxynitrite diminishes myogenic tone in cerebral arteries: role of nitrotyrosine and F-actin. Am J Physiol 292:H1042-50.

Cipolla MJ, DeLance N and Vitullo L (2006). Pregnancy prevents hypertensive remodeling of cerebral arteries: a potential role in the development of eclampsia. Hypertension 47:619-26.

Maneen M, Hannah R, Vitullo L, DeLance N and Cipolla M (2006). Peroxynitrite diminishes myogenic tone and promotes loss of reactivity in rat posterior cerebral arteries. Stroke 37:894-9.

Cipolla MJ, Vitullo L, DeLance N, and Hammer E (2005). The cerebral endothelium during pregnancy: A potential role in the development of eclampsia. Endothelium 12:1-5.

Euser A and Cipolla MJ (2005). Resistance artery vasodilation to magnesium sulfate during pregnancy and the postpartum state. Am J Physiol 288:H1521-H1525.

Quick AM and Cipolla MJ (2005). Pregnancy-induced upregulation of aquaporin-4 protein in brain and its role in eclampsia. FASEB J 19:170-175.

• Cipolla web page in Neurology
• Cipolla web page in Pharmacology