Mechanical activation of signaling pathways in the cardiovascular system

Mechanical forces are constantly exerting stress upon the tissues and cells of the cardiovascular system. To influence the biology of cells, these stimuli, which exist in the physical domain, must be converted into signals in the biochemical language of the cells. This process has been referred to as mechano-chemical signal transduction, or mechanotransduction. Although a great deal is known about which aspects of cardiovascular biology are influenced or dictated by physical forces, a great deal of uncertainty exists about which of the many signaling pathways that respond in cardiovascular cells to mechanical stimuli specifically regulate mechanosensitive aspects of the "cardiovascular phenotype". Even less is known regarding the identity and function of structures and catalysts that operate at the physical-biochemical interface and act to convert physical energy into signals of biological relevance. This article presents what is known regarding signaling pathways in cells of the cardiovascular system, which have been shown empirically to respond to mechanical stimuli, and what can be inferred from biochemical and pharmacological studies in cultured cardiovascular cells regarding the potential for certain signaling pathways to be involved in the manifestation of mechanically responsive phenotypes in the cardiovascular system.     

Nitric oxide signaling in the cardiovascular system: implications for heart failure

PURPOSE OF REVIEW: The role played by nitric oxide (NO) in cardiovascular physiology remains highly controversial. Following the discovery that NO is the prototypic endothelium-derived relaxing factor, this signaling molecule was implicated as possessing many other biological actions within the cardiovascular system, including effects on cardiac contraction, relaxation, and energetics. Here, we discuss new concepts regarding NO signaling, its effector pathways, and interactions between NO and the redox milieu within a framework of cardiac physiology and pathophysiology. RECENT FINDINGS: Major recent insights that have advanced understanding of the mechanisms of NO bioactivity include the following. (1) NO acts in subcellular signaling compartments or modules. (2) S-nitrosylation (covalent modification of cysteine thiol moieties) of proteins represents a prototypic second messenger signaling mode in biologic systems. (3) Reactive oxygen and nitrogen species work together to facilitate signaling. (4) Disruption of physiologic signaling can occur by either increased formation of reactive oxygen species or decreased production of reactive nitrogen species, a situation of nitroso-redox imbalance. SUMMARY: These insights, which challenge classically held views that NO acts as a freely diffusible molecule regulated primarily by concentration and exerting signaling primarily through cyclic GMP production, offer a new perspective on the pathophysiology and treatment of congestive heart failure.     

Circulating cardiovascular disease risk factors and signaling in endothelial cell caveolae

Caveolae are a subset of lipid rafts that are prevalent on the plasma membrane of endothelial cells. They compartmentalize signal transduction molecules which regulate multiple endothelial functions including the production of nitric oxide (NO) by the caveolae resident enzyme endothelial NO synthase (eNOS). Recent studies have demonstrated that circulating factors known to modify cardiovascular disease risk regulate signaling in endothelial cell caveolae. In particular, high density lipoprotein (HDL) maintains the lipid environment in caveolae, thereby promoting the retention and function of eNOS in the domain, and it also causes direct activation of eNOS via scavenger receptor type BI (SR-BI)-induced kinase signaling. Estrogen binding to estrogen receptors (ER) in caveolae also activates eNOS, and this occurs through G protein and kinase activation. Discrete domains within SR-BI and ER mediating signal initiation in caveolae have been identified. Counteracting the promodulatory actions of HDL and estrogen, C-reactive protein (CRP) antagonizes eNOS through FcgammaRIIB and PP2A, which dephosphorylates and inactivates the enzyme. The endothelial cell functions modified by these processes include the regulation of monocyte adhesion and endothelial cell migration. Thus, signaling events in caveolae invoked by known circulating cardiovascular disease risk factors have major impact on endothelial cell phenotypes of importance to cardiovascular health and disease.     

Redox signaling in angiogenesis: role of NADPH oxidase

Angiogenesis, a process of new blood vessel formation, is a key process involved in normal development and wound repair as well as in the various pathophysiologies such as ischemic heart and limb diseases and atherosclerosis. Reactive oxygen species (ROS) such as superoxide and H(2)O(2) function as signaling molecules in many aspects of growth factor-mediated responses including angiogenesis. Vascular endothelial growth factor (VEGF) is a key angiogenic growth factor and stimulates proliferation, migration, and tube formation of endothelial cells (ECs) primarily through the VEGF receptor type2 (VEGR2, KDR/Flk1). VEGF binding initiates autophosphorylation of VEGFR2, which results in activation of downstream signaling enzymes including ERK1/2, Akt, and eNOS in ECs, thereby stimulating angiogenesis. The major source of ROS in EC is a NADPH oxidase which consists of Nox1, Nox2 (gp91phox), Nox4, p22phox, p47phox, p67phox and the small G protein Rac1. The endothelial NADPH oxidase is activated by angiogenic factors including VEGF and angiopoietin-1. ROS derived from this enzyme stimulate diverse redox signaling pathways leading to angiogenesis-related gene induction as well as EC migration and proliferation, which may contribute to postnatal angiogenesis in vivo. The aim of this review is to provide an overview of the recent progress on the emerging area of the role of ROS derived from NADPH oxidase and redox signaling in angiogenesis. Understanding these mechanisms may provide insight into the NADPH oxidase and redox signaling components as potential therapeutic targets for treatment of angiogenesis-dependent cardiovascular diseases and for promoting angiogenesis in ischemic limb and heart diseases.     

Therapeutic modification of the L-arginine-eNOS pathway in cardiovascular diseases

L-Arginine is the substrate for nitric oxide production. Endothelium dysfunction could be attributed to L-arginine deficiency or the presence of L-arginine endogenous inhibitors. This hypothesis leads to the assumption that provision of L-arginine could be the key for endothelial function improvement. Many studies have proven that L-arginine has a beneficial effect on endothelium dependent vasoreactivity, as well as on the interaction between vascular wall, platelets and leucocytes. Therefore, individuals with risk factors for atherosclerosis and patients with coronary artery disease or heart failure, could benefit from therapy with L-arginine.     

Self-organization of the phosphatidylinositol lipids signaling system for random cell migration

Phosphatidylinositol (PtdIns) lipids have been identified as key signaling mediators for random cell migration as well as chemoattractant-induced directional migration. However, how the PtdIns lipids are organized spatiotemporally to regulate cellular motility and polarity remains to be clarified. Here, we found that self-organized waves of PtdIns 3,4,5-trisphosphate [PtdIns(3,4,5)P₃] are generated spontaneously on the membrane of Dictyostelium cells in the absence of a chemoattractant. Characteristic oscillatory dynamics within the PtdIns lipids signaling system were determined experimentally by observing the phenotypic variability of PtdIns lipid waves in single cells, which exhibited characteristics of a relaxation oscillator. The enzymes phosphatase and tensin homolog (PTEN) and phosphoinositide-3-kinase (PI3K), which are regulators for PtdIns lipid concentrations along the membrane, were essential for wave generation whereas functional actin cytoskeleton was not. Defects in these enzymes inhibited wave generation as well as actin-based polarization and cell migration. On the basis of these experimental results, we developed a reaction-diffusion model that reproduced the characteristic relaxation oscillation dynamics of the PtdIns lipid system, illustrating that a self-organization mechanism provides the basis for the PtdIns lipids signaling system to generate spontaneous spatiotemporal signals for random cell migration and that molecular noise derived from stochastic fluctuations within the signaling components gives rise to the variability of these spontaneous signals.