Pulmonary arterial hypertension (PAH) has a multifactorial pathobiology. Vasoconstriction, remodeling of the pulmonary vessel wall, and thrombosis contribute to increased pulmonary vascular resistance in PAH. The process of pulmonary vascular remodeling involves all layers of the vessel wall and is complicated by cellular heterogeneity within each compartment of the pulmonary arterial wall. Indeed, each cell type (endothelial, smooth muscle, and fibroblast), as well as inflammatory cells and platelets, may play a significant role in PAH. Pulmonary vasoconstriction is believed to be an early component of the pulmonary hypertensive process. Excessive vasoconstriction has been related to abnormal function or expression of potassium channels and to endothelial dysfunction. Endothelial dysfunction leads to chronically impaired production of vasodilators such as nitric oxide and prostacyclin along with overexpression of vasoconstrictors such as endothelin (ET)-1. Many of these abnormalities not only elevate vascular tone and promote vascular remodeling but also represent logical pharmacological targets. Recent genetic and pathophysiologic studies have emphasized the relevance of several mediators in this condition, including prostacyclin, nitric oxide, ET-1, angiopoietin-1, serotonin, cytokines, chemokines, and members of the transforming-growth-factor-beta superfamily. Disordered proteolysis of the extracellular matrix is also evident in PAH. Future studies are required to find which if any of these abnormalities initiates PAH and which ones are best targeted to cure the disease.

Pulmonary arterial hypertension (PAH) is caused by functional and structural changes in the pulmonary vasculature, leading to increased pulmonary vascular resistance. The process of pulmonary vascular remodeling is accompanied by endothelial dysfunction, activation of fibroblasts and smooth muscle cells, crosstalk between cells within the vascular wall, and recruitment of circulating progenitor cells. Recent findings have reestablished the role of chronic vasoconstriction in the remodeling process. Although the pathology of PAH in the lung is well known, this article is concerned with the cellular and molecular processes involved. In particular we focus on the role of the Rho family guanosine triphosphatases in endothelial function and vasoconstriction. The crosstalk between endothelium and vascular smooth muscle is explored in the context of mutations in the bone morphogenetic protein type II receptor, alterations in angiopoietin-1/TIE2 signaling and the serotonin pathway. We also review the role of voltage-gated K+ (Kv) channels and transient receptor potential channels in the regulation of cytosolic [Ca2+] and [K+], vasoconstriction, proliferation and cell survival. We highlight the importance of the extracellular matrix as an active regulator of cell behavior and phenotype and evaluate the contribution of the glycoprotein tenascin-c as a key mediator of smooth muscle cell growth and survival. Finally, we discuss the origins of a cell type critical to the process of pulmonary vascular remodeling, the myofibroblast, and review the evidence supporting a contribution for the involvement of endothelial-mesenchymal transition and recruitment of circulating mesenchymal progenitor cells.

Analysis of extracts of Glen Ample raspberries (Rubus idaeus L.) by gradient, reverse phase HPLC with diode array and tandem mass spectrometry identified eleven anthocyanins, including cyanidin-3-sophoroside, cyanidin-3-(2(G)-glucosylrutinoside), cyanidin-3-glucoside, cyanidin-3-rutinoside, pelargonidin-3-sophoroside, pelargonidin-3-(2(G)-glucosylrutinoside), and pelargonidin-3-glucoside. Significant quantities of an ellagitannin, sanguiin H-6, with an M(r) of 1870 were detected along with lower levels of a second ellagitannin, lambertianin C, which has an M(r) of 2804. Other phenolic compounds that were detected included trace levels of ellagic acid and its sugar conjugates along with one kaempferol- and four quercetin-based flavonol conjugates. Fractionation by preparative HPLC revealed that sanguiin H-6 was a major contributor to the antioxidant capacity of raspberries together with vitamin C and the anthocyanins. Vasodilation activity was restricted to fractions containing lambertianin C and sanguiin H-6.

Objective-MicroRNAs (miRNAs) are small noncoding RNAs that have the capacity to control protein production through binding "seed" sequences within a target mRNA. Each miRNA is capable of potentially controlling hundreds of genes. The regulation of miRNAs in the lung during the development of pulmonary arterial hypertension (PAH) is unknown. Methods and Results-We screened lung miRNA profiles in a longitudinal and crossover design during the development of PAH caused by chronic hypoxia or monocrotaline in rats. We identified reduced expression of Dicer, involved in miRNA processing, during the onset of PAH after hypoxia. MiR-22, miR-30, and let-7f were downregulated, whereas miR-322 and miR-451 were upregulated significantly during the development of PAH in both models. Differences were observed between monocrotaline and chronic hypoxia. For example, miR-21 and let-7a were significantly reduced only in monocrotaline-treated rats. MiRNAs that were significantly regulated were validated by quantitative polymerase chain reaction. By using in vitro studies, we demonstrated that hypoxia and growth factors implicated in PAH induced similar changes in miRNA expression. Furthermore, we confirmed miR-21 downregulation in human lung tissue and serum from patients with idiopathic PAH. Conclusion-Defined miRNAs are regulated during the development of PAH in rats. Therefore, miRNAs may contribute to the pathogenesis of PAH and represent a novel opportunity for therapeutic intervention. Key Words: pulmonary hypertension Ⅲ small RNA molecules Ⅲ gene regulation P ulmonary arterial hypertension (PAH) is a complex disorder characterized by the obstructive remodeling of pulmonary arteries, leading to a progressive elevation in pulmonary arterial pressure (PAP) and subsequent right-sided heart failure and death. 1 Familial PAH is associated in 80% of cases with diverse heterozygous mutations in the gene-encoding bone morphogenetic protein receptor 2 (BMPR-II) 2 and can be associated with mutations in the activin-receptor kinaselike 1 gene. 3 The cause of the variable phenotypic expression of PAH among carriers of mutated BMPR-II genes is unclear, and is likely related to environmental and genetic modifiers. Although BMPR-II-related pathways are considered pivotal, many other mediator pathways participate in the pathogenesis of PAH and are being actively investigated, both independently and in combination. For example, the involvement of serotonin in the development of experimental PAH has been recently reported. 4,5 Indeed, important interactions between the serotonin and BMP pathways have recently been described. 6 Rats exposed to hypoxia or injected with the toxin monocrotaline develop pulmonary arterial changes correlated with the development of PAH, including remodeling and elevating PAP.MicroRNAs (miRNAs) are small noncoding transcripts of 16 to 29 nucleotide RNAs that regulate gene expression posttranscriptionally by targeting mRNAs. Animal miRNAs are processed from longer primary transcripts (primary miRNAs) that can contain ...