Vascular remodeling is an adaptive mechanism for long-term modification of vascular diameter. In hypertension, inward remodeling, that is, the structural reduction of the lumen diameter in resistance vessels, is associated with an increased risk for myocardial infarction and stroke. However, despite its association with life threatening cardiovascular events, little is known about the mechanisms that initiate and guide the progression of inward remodeling in the resistance microvessels. In this regard, we view the remodeling process as a continuum of events that culminate in the structurally altered vessel. Our singularly novel and provocative hypothesis is that sustained arteriolar vasoconstriction in response to prolonged humoral, and/or mechanical stimuli initiates remodeling mechanisms characterized by: 1) partial degradation (turnover) of the extracellular matrix (ECM) components of the vessel wall;2) rearrangement of the vascular smooth muscle (VSM) cytoskeleton;and 3) repositioning of the VSM cellular attachments via processes that depend on the cellular production of reactive oxygen species (ROS). Using a highly innovative multiphoton imaging technique developed in our laboratories, we recently demonstrated that VSM cells in isolated arterioles re-lengthen and rapidly change position during prolonged vasoconstriction (a hallmark of hypertension) while the reduced arteriolar diameter is maintained. This phenomenon occurs in as little as four hours, and we propose is an early mechanism associated with inward remodeling. We further hypothesize that other mechanisms occur concurrently, including: 1) ROS-dependent activation of matrix metalloproteinases (MMP) to degrade the ECM;2) ROS-dependent modulation of the small G protein Rho to induce calcium sensitization and remodel the VSM cytoskeleton;and 3) ROS-dependent modulation of integrin-dependent VSM cell attachments. We will test our hypotheses in three in vivo and two in vitro models using state of the art imaging and molecular approaches. With intravital microscopy we will monitor vascular remodeling in vivo, and with multiphoton microscopy, we will determine VSM cell behavior and ECM changes in isolated arterioles. With atomic force microscopy (AFM) and fluorescence imaging we will apply discrete forces to freshly isolated VSM cells and monitor focal adhesion (cellular attachments) and cytoskeletal remodeling. These methodologies combined with molecular and pharmacological techniques will be used in our Specific Aims to determine the role of ROS, MMPs, Rho, and integrins on remodeling. These approaches will provide a powerful strategy for testing our hypotheses and integrating our results. Our long-term goal is to characterize the mechanisms leading to the structural modification of resistance vessels in hypertension. These fundamentally important mechanistic studies will allow us to develop new strategies to prevent, stop, and/or reverse remodeling and the life threatening events associated with it.
Public Health Relevance Statement In people with high blood pressure, the small blood vessels known as resistance arterioles undergo a process of structural remodeling that reduces their internal diameter and increases the risk for heart attacks and stroke. The goal of this project is to understand the mechanisms that control this remodeling. This understanding will allow us to develop novel strategies for preventing, stopping, and/or reversing the remodeling process and the life threatening events that are associated with it.
|Padilla, Jaume; Ramirez-Perez, Francisco I; Habibi, Javad et al. (2016) Regular Exercise Reduces Endothelial Cortical Stiffness in Western Diet-Fed Female Mice. Hypertension 68:1236-1244|
|Foote, Christopher A; Castorena-Gonzalez, Jorge A; Ramirez-Perez, Francisco I et al. (2016) Arterial Stiffening in Western Diet-Fed Mice Is Associated with Increased Vascular Elastin, Transforming Growth Factor-Î², and Plasma Neuraminidase. Front Physiol 7:285|
|Manrique, Camila; Habibi, Javad; Aroor, Annayya R et al. (2016) Dipeptidyl peptidase-4 inhibition with linagliptin prevents western diet-induced vascular abnormalities in female mice. Cardiovasc Diabetol 15:94|
|Pennington, Kathleen A; Ramirez-Perez, Francisco I; Pollock, Kelly E et al. (2016) Maternal Hyperleptinemia Is Associated with Male Offspring's Altered Vascular Function and Structure in Mice. PLoS One 11:e0155377|
|Foote, Christopher A; Castorena-Gonzalez, Jorge A; Staiculescu, Marius C et al. (2016) Brief serotonin exposure initiates arteriolar inward remodeling processes in vivo that involve transglutaminase activation and actin cytoskeleton reorganization. Am J Physiol Heart Circ Physiol 310:H188-98|
|Jia, Guanghong; Aroor, Annayya R; Martinez-Lemus, Luis A et al. (2015) Mitochondrial functional impairment in response to environmental toxins in the cardiorenal metabolic syndrome. Arch Toxicol 89:147-53|
|DeMarco, Vincent G; Habibi, Javad; Jia, Guanghong et al. (2015) Low-Dose Mineralocorticoid Receptor Blockade Prevents Western Diet-Induced Arterial Stiffening in Female Mice. Hypertension 66:99-107|
|Bender, Shawn B; Castorena-Gonzalez, Jorge A; Garro, Mona et al. (2015) Regional variation in arterial stiffening and dysfunction in Western diet-induced obesity. Am J Physiol Heart Circ Physiol 309:H574-82|
|Castorena-Gonzalez, Jorge A; Staiculescu, Marius C; Foote, Christopher A et al. (2014) The obligatory role of the actin cytoskeleton on inward remodeling induced by dithiothreitol activation of endogenous transglutaminase in isolated arterioles. Am J Physiol Heart Circ Physiol 306:H485-95|
|Ramirez-Perez, Francisco I; Schenewerk, Angela L; Coffman, Katy L et al. (2014) Effects of the use of assisted reproductive technologies and an obesogenic environment on resistance artery function and diabetes biomarkers in mice offspring. PLoS One 9:e112651|
Showing the most recent 10 out of 23 publications