Wamhoff, Brian R.

Brian R. Wamhoff

Brian R. Wamhoff

Primary Appointment

Assistant Professor, Medicine: Cardiovascular Medicine


  • PhD, University of Missouri

Contact Information

MR-4, Room 6022
Charlottesville, VA 22908
Telephone: 243-6525
Email: wamhoff@virginia.edu

Research Interests

Atherosclerosis/Restenosis; Excitation Transcription Coupling; Biomedical Models of Vascular Disease.

Research Description

The Wamhoff lab is primarily focused on a disease called atherosclerosis, a disease that is responsible for more than 50% of all deaths in the Untied States. We specifically study the vascular smooth muscle cell (SMC) which forms the muscular layers of the vessel wall and regulates contraction and tone. The SMC also plays a critical role in the pathogenesis of atherosclerosis. In atherosclerosis, healthy/contractile SMCs can undergo phenotype modulation, showing high rates of proliferation and migration which, in cooperation with several other cell types, leads to blood vessel narrowing and stenosis. Luminal narrowing can compromise blood flow to the heart, for example, leading to myocardial ischemia or a heart attack. Revascularization of the atherosclerotic blood vessel is accomplished clinically by balloon angioplasty and deployment of a wire mesh stent to restore blood flow. A major potential adverse effect of stenting is acute injury to the vessel which can lead to in-stent restenosis; a new lesion that is rich in SMCs. Thus, the primary focus of our research is to determine mechanisms that regulate smooth muscle cell (SMC) phenotypic modulation in response to atherosclerotic stimuli and acute vascular injury.
The research aims of our funding are directly related to the 3 BIMS programs of which I am a faculty member: Molecular Medicine, Biomedical Engineering and Biochemistry, Molecular Biology and Genetics. We employ the use of several highly innovative techniques:

  • laser capture microdissection

  • mouse Cre/lox technology for in vivo gene mutagenesis

  • novel in vivo vascular injury and atherosclerosis models

  • biomedical models/devices that mimic the artery in vitro

  • derivation of SMCs from adult and embryonic stem cells

  • novel pharmacological reagents to target SMC phenotypic modulation

  • classic molecular biology techniques

  • classic vascular physiology techniques

This integrated approach to understanding vascular SMC phenotypic modulation allows us to fully understand the disease process from the DNA level in vitro to the whole animal level in vivo with a strong emphasis of translating our finding to real human translational events.
We are currently focused intensely on 3 mechanisms that regulate SMC phenotypic modulation:
Calcium (Ca) – Ca plays a critical role in regulating the contractile state of the SMC. Ca is also an important regulator of SMC transcriptional events. These events are regulated through a process coined Excitation-Transcription-Coupling (ETC). ETC involves multiple ion channels and intracellular Ca regulatory proteins that, depending on the specific signaling molecule, ultimately activate a specific gene repertoire in the SMC. Our overall hypothesis for this project is that Ca-dependent molecular mechanisms regulate SMC phenotype during SMC development and maintenance of the contractile phenotype, and that these control mechanisms are altered during phenotypic modulation associated with atherosclerosis.
Sphingosine-1-phosphate (S1P) – S1P is a bioactive phospholipid that is primarily stored in platelets. Platelets play a key role in the response to acute vascular injury. S1P signals through multiple G-protein coupled receptors whose signaling endpoints are unique, including altering intracellular Ca. Our overall hypothesis is that selectiveS1P receptor signaling promotes SMC differentiation marker gene expression in mature/contractile SMCs and that vascular injury disrupts this process thus promoting SMC phenotypic modulation, proliferation and stenosis.
Endothelial cells (EC) – There is unequivocal evidence demonstrating that various forms of insult to the endothelial cell (EC) layer lead to subsequent SMC phenotypic modulation resulting in SMC proliferation and atherosclerotic lesion formation. Thus, the delicate balance of positive and negative cross-talk between ECs and SMCs is proposed to be critical for maintaining homeostasis in the vessel wall. In collaboration with Dr. Brett Blackman (BME), we have developed an in vitro human EC-SMC co-culture model capable of imposing human vessel-derived hemodynamic flow patterns to the endothelial cell layer to determine the effects of cardioprotective and atherosclerotic prone hemodynamic flow patterns on EC and SMC phenotypic modulation.

Selected Publications