Small GTPases and Their Role in Vascular Disease

Abstract

Over eighty million people in the United States have cardiovascular disease that can affect the heart causing myocardial infarction; the carotid arteries causing stroke; and the lower extremities leading to amputation. The treatment for end-stage cardiovascular disease is surgical—either endovascular therapy with balloons and stents—or open reconstruction to reestablish blood flow. All interventions damage or destroy the protective inner lining of the blood vessel—the endothelium. An intact endothelium is essential to provide a protective; antithrombotic lining of a blood vessel. Currently; there are no agents used in the clinical setting that promote reendothelialization. This process requires migration of endothelial cells to the denuded vessel; proliferation of endothelial cells on the denuded vessel surface; and the reconstitution of the tight adherence junctions responsible for the formation of an impermeable surface. These processes are all regulated in part and are dependent on small GTPases. As important as the small GTPases are for reendothelialization, dysregulation of these molecules can result in various vascular pathologies including aneurysm formation, atherosclerosis, diabetes, angiogenesis, and hypertension. A better understanding of the role of small GTPases in endothelial cell migration is essential to the development for novel agents to treat vascular disease.

Small Vessel Disease-Related Dementia: An Invalid Neurovascular Coupling?

“…The reduction of NO production is derived from an impairment of the mitochondrial functions, being caused by a hyperproduction of the anti-oxidative defense system, and an increased O2 anions reaction with NO, producing peroxynitrite [215]. The activity of endothelial NO synthase (eNOS), which catalyzes the production of NO, declines with aging [216], but is even more impaired in SVD, where an important downstream target of Rho is the Rho-associated protein kinase (ROCK) [217]. These ubiquitously expressed serine/threonine protein kinases are involved in diverse cellular activities, including apoptosis, smooth muscle contraction, cell adhesion, and remodeling of the extracellular matrix [218].…”

“…These ubiquitously expressed serine/threonine protein kinases are involved in diverse cellular activities, including apoptosis, smooth muscle contraction, cell adhesion, and remodeling of the extracellular matrix [218]. In the regulation of endothelial cell, migration ROCK interacts with ezrin, radixin, and moesin (also known as the ERM proteins) that function as cross-linkers between the plasma membrane and actin filaments [217] and are indispensable for the leukocyte adhesion molecules coordination, being essential for barrier function [219]. Moreover, the ROCK/RhoA complex regulates the eNOS, as previously exposed [217].…”

“…In the regulation of endothelial cell, migration ROCK interacts with ezrin, radixin, and moesin (also known as the ERM proteins) that function as cross-linkers between the plasma membrane and actin filaments [217] and are indispensable for the leukocyte adhesion molecules coordination, being essential for barrier function [219]. Moreover, the ROCK/RhoA complex regulates the eNOS, as previously exposed [217]. NO-induced vasodilation occurs via the activation of myosin light chain phosphatase (MLCP) in a cGMP dependent manner.…”

“…NO-induced vasodilation occurs via the activation of myosin light chain phosphatase (MLCP) in a cGMP dependent manner. RhoA/ROCK counteracts this through MLCP inactivation and calcium desensitization [217,220]. ROCK/Rho decreases eNOS expression and affects the availability of NO [221]; it has also been proven in brain small vessels, even if these effects have been largely studied in major vessel disease (coronary) [82].…”

Diverse Physiological Functions and Regulatory Mechanisms for Signal-Transducing Small GTPases

“…The specific contribution of the deregulation of the Rac protein in hematologic malignancies was described in detail. Flentje et al [ 15 ] summarized the role of Rho family small GTPases in the process of endothelium reconstruction after surgical treatments for cardiovascular disease. The process includes the migration and proliferation of endothelial cells, and a better understanding of the role for small GTPases in endothelial cell migration and proliferation may lead to the development of novel agents to treat vascular disease.…”