Current Vascular Pharmacology - Volume 5, Issue 1, 2007

Guanosine-dependent cyclic nucleotide second messenger signaling has been implicated as a pivotal mediator of vascular function under both homeostatic eutrophic conditions as well as in the inimical environs of injury and/or disease. This biological system is highly regulated through reciprocal, complimentary, and often redundant upstream and downstream molecular and cellular elements and feedback controls. Key endogenous factors of the guanosine-dependent cyclic nucleotide cascade include upstream gaseous activating ligands (nitric oxide, carbon monoxide), downstream substrates (cGMP-gated ion channels, cGMP-dependent protein kinases), and cGMP hydrolyzing phosphodiesterases. This intricate system also has capacity to “cross-talk” with parallel adenosine-dependent cyclic nucleotide machinery. Numerous complexes of ligands, enzymes, cofactors, and substrates present significant targets for pharmacologic modulation at the cellular, genetic, and/or molecular level eventuating therapeutically as constructive functional responses observed in vascular physiology and/or pathophysiology. Interestingly, emerging evidence based largely on transgenic mouse models challenges the historically accepted concept that this signaling system functions principally as a therapeutic modality in cardiac and vascular tissues. The general purpose of this update is to provide current information on recently described neoteric agents that impact multifaceted and critical cGMP-dependent signaling in the vascular system. Emphasis will be placed on novel agents that exert significant and often multiple actions on upstream and downstream sites and are capable of eliciting robust effects on guanosine-dependent cellular actions. Individual sections will be devoted to agents that rely on an intact and functional cyclase heme and those that operate independently of the sGC heme. Attention will be placed on the physiologic and pathophysiologic clinical manifestations of these pharmacologic regimens. This review will conclude with some thoughts for future directions for study and continued discovery of novel sGC/cGMP controllers in the vascular system at the basic science and clinical levels.

Biomarkers are used in medicine to facilitate diagnosis, assess risk, direct therapy and determine efficacy of treatment. Sensitivity and specificity are essential in order for a biomarker to be useful. Brain natriuretic peptide (BNP) and C-reactive protein (CRP) are considered biomarkers of cardiovascular disease. However, they differ in function, sensitivity and specificity. BNP is released from the myocardium in response to myocardial stretch, a clear cause and effect relationship; therefore, it is useful in the diagnosis of heart failure when patients present with dyspnea of unknown origin and to assess treatment in high risk patients with diagnosed heart failure. Sex and age based reference ranges and partition values are established from clinical trials and from populations screened for the absence of cardiovascular disease. Highly sensitive and reproducible methods are also available to measure CRP. However, although CRP is associated with adverse cardiovascular events, unlike BNP, multiple stimuli increase production of CRP. Therefore, elevation in CRP is not specific to cardiovascular disease. Partition values for CRP and cardiovascular risk based on epidemiological studies predict risk for populations but may not always be useful when used alone to predict individual risk or to direct therapy. Given the non-specific stimuli which affect circulating concentrations of CRP, using CRP to monitor treatment to reduce cardiovascular risk may provide little benefit without understanding or targeting the underlying causes for its elevation.

The heart does not mend itself after infarction. However, stem cells may revolutionize heart disease treatment. A vast and growing body of evidence indicates that cell-based strategies have promising therapeutic potential. Recent clinical and pre-clinical studies demonstrate varying degrees of improvement in cardiac function using different adult stem cell types such as bone marrow (BM)-derived progenitor cells and skeletal myoblasts. However, the efficacy of cell therapy after myocardial infarction (MI) is inconclusive and the cellular source with the highest potential for regeneration is unclear. Clinically, BM and skeletal muscle are the most commonly used sources of autologous stem cells. One major pitfall of using autologous stem cells is that the number of functional cells is generally depleted in the elderly and chronically ill. Therefore, there is an urgent need for a new source of adult stem cells. Human umbilical cord blood (CB) is a candidate and appears to have several key advantages. CB is a viable and practical source of progenitor cells. The cells are naïve and what's more, CB contains a higher number of immature stem/progenitor cells than BM. We review recent clinical experience with adult stem cells and explore the potential of CB as a source of cells for cardiac repair following MI. We conclude that there is a conspicuous absence of clinical studies utilizing CB-derived cells and there is a pressing need for large randomized double-blinded clinical trials to assess the overall efficacy of cell-based therapy.

Endothelin-1 (ET-1), a vasoactive peptide, is believed to contribute to the pathogenesis of vascular abnormalities such as hypertension, atherosclerosis, hypertrophy and restenosis. ET-1 elicits its biological effects through the activation of two receptor subtypes, ET-A and ET-B that belong to a large family of transmembrane guanine nucleotide-binding protein-coupled receptors (GPCRs). ET-1 receptor activation results in the stimulation of several signaling pathways including mitogen-activated protein kinases (MAPKs), phosphatidylinositol 3-kinase (PI3-K) and protein kinase B (PKB). An intermediary role of Ca2+/calmodulin-dependent protein kinases (CaMK), protein kinase C (PKC) as well as receptor and non-receptor protein tyrosine kinases in triggering the activation of MAPK and PI3-K/PKB signaling in response to ET-1 has been suggested. Activation of these pathways by ET-1 is intimately linked with the regulation of cellular hypertrophy, growth, proliferation and cell survival. Here we provide an overview of these signaling pathways in vascular smooth muscle cells (VSMCs) with an emphasis on their potential role in vascular pathophysiology.

A variety of optical techniques have been developed over the years for experimental use in vascular disease, mainly for the assessment of lower limb peripheral arterial disease (PAD). Optical techniques have several advantages over more traditional experimental approaches. Photoplethysmograph (PPG) was one of the earliest methods used for this purpose; PPG satisfies many of the conditions for a non-invasive technique to estimate skin blood flow using infrared light, not only for research but also in clinical practice. PPG is a promising, safe and easy-to-use tool for diagnosis and early screening of various atherosclerotic pathologies and could be useful for regular GP-assessment or even selfmonitoring of PAD at home or during individual physical exercises. This review discusses the application of PPG in the assessment of PAD.

Vascular disease is primarily the result of atherosclerosis which affects all layers of the adult vessel wall. Our understanding of atherosclerosis has evolved over the past three decades; from initial hypotheses based on lipid deposition and fibrocellular proliferation within the intima of the vessel wall to a more complex interplay between conventional risk factors, inflammation and the immune system implicating pan-vascular biologic processes. More recently circulating progenitor cells have been shown to possess diverse differentiation capacity within the remodelling vessel wall. Current investigation of atherosclerosis therefore encompasses an expanding field of biological science; from molecular genetics, classical vascular biology, and immunology to stem cell biology and vasculogenesis. However, a decade after their initial description, scientists still know little about the proximate relationship between vascular progenitor cells and atherosclerosis progression or stability. In recent years, the discovery of progenitor cells of myeloid origin has offered the exciting prospect of merging classical concepts of myeloid cell biology in atherosclerosis with evolving concepts of myeloid cell plasticity and endothelial / smooth muscle cells differentiation within the injured vessel wall. In this context, early stage atherosclerosis associated with vascular injury may involve neovascularisation and re-endothelialisation in which a significant contribution comes from bone marrow-derived vascular progenitor cells. For this review, emphasis will be on endothelial progenitor cells (EPC), smooth muscle progenitor cells (SPC) and putative myeloid precursors.

Gestational diabetes (GD, characterized by abnormal D-glucose metabolism), intrauterine growth restriction (IUGR, a disease associated with reduced oxygen delivery (hypoxia) to the foetus), and preeclampsia (PE, a pregnancy complication characterized by high blood pressure, proteinuria and increased vascular resistance), induce foetal endothelial dysfunction with implications in adult life and increase the risk of vascular diseases. Synthesis of nitric oxide (NO) and uptake of L-arginine (the NO synthase (NOS) substrate) and adenosine (a vasoactive endogenous nucleoside) by the umbilical vein endothelium is altered in pregnancies with GD, IUGR or PE. Mechanisms underlying these alterations include differential expression of equilibrative nucleoside transporters (ENTs), cationic amino acid transporters (CATs), and NOS. Modulation of ENTs, CATs, and NOS expression and activity in endothelium involves protein kinase C (PKC), mitogen- activated protein kinases p42 and p44 (p42/44mapk), calcium, and phosphatidyl inositol 3 kinase (PI3k), among others. Elevated extracellular D-glucose and hypoxia alter human endothelial function. However, information regarding the transcriptional modulation of ENTs, CATs, and NOS is limited. This review focuses on the effect of transcriptional and post-transcriptional regulatory mechanisms involved in the modulation of ENTs and CATs, and NOS expression and activity, and the consequences for foetal endothelial function in GD, IUGR and PE. The available information will contribute to a better understanding of the cell and molecular basis of the altered vascular endothelial function in these pregnancy diseases and will emphasize the key role of this type of epithelium in placental function and the normal foetal development and growth.

Although nitric oxide (NO) is recognized as the primary vasodilator derived from vascular endothelium in regulating the vascular tone, another factor, i.e. the endothelium-derived hyperpolarizing factor (EDHF), has recently gained much attention and has been demonstrated to participate in vasodilatation in various blood vessels from different species, despite its unidentified nature. Most of the studies were conducted in animals and the knowledge of this factor in the human vasculature is relatively limited. This review attempts to address the relevance of EDHF-mediated function in humans with the possible identity of EDHF and mechanisms involved. We consider the human vasculature where EDHF involvement has been documented including the systemic, coronary, and visceral (gastrointestinal, renal and reproductive) circulation. In these vascular systems, EDHF plays a role under physiological conditions either as another mechanism or as the “back-up” for NO. Furthermore, the contribution of EDHF changes under certain physiological conditions, such as ageing and pregnancy. In addition, altered EDHF function has been suggested in various pathological conditions including heart diseases, atherosclerosis, hypertension, diabetes, eclampsia, glaucoma, chronic renal failure, erectile dysfunction and ischemia-reperfusion period during open heart surgery. Pharmacological agents such as potassium channel openers or cytochrome P450 metabolites have been used to either protect or recover EDHF-dependent mechanisms. To further develop new therapeutic strategies that target EDHF, a better understanding is essential with regard to the function of EDHF under pathophysiological conditions in humans. Furthermore, the interaction between NO and EDHF as well as their relative contributions in various conditions are critical.