Enhanced α₁-adrenergic trophic activity in pulmonary artery of hypoxic pulmonary hypertensive rats

Abstract

. Enhanced ␣1-adrenergic trophic activity in pulmonary artery of hypoxic pulmonary hypertensive rats. Am J Physiol Heart Circ Physiol 291: H2272-H2281, 2006. First published June 23, 2006 doi:10.1152/ajpheart.00404.2006.-Mechanisms that induce the excessive proliferation of vascular wall cells in hypoxic pulmonary hypertension (PH) are not fully understood. Alveolar hypoxia causes sympathoexcitation, and norepinephrine can stimulate ␣1-adrenoceptor (␣1-AR)-dependent hypertrophy/hyperplasia of smooth muscle cells and adventitial fibroblasts. Adrenergic trophic activity is augmented in systemic arteries by injury and altered shear stress, which are key pathogenic stimuli in hypoxic PH, and contributes to neointimal formation and flow-mediated hypertrophic remodeling. Here we examined whether norepinephrine stimulates growth of the pulmonary artery (PA) and whether this is augmented in PH. PA from normoxic and hypoxic rats [9 days of 0.1 fraction of inspired O2 (FIO 2 )] was studied in organ culture, where wall tension, PO2, and PCO2 were maintained at values present in normal and hypoxic PH rats. Norepinephrine treatment for 72 h increased DNA and protein content modestly in normoxic PA (ϩ10%, P Ͻ 0.05). In hypoxic PA, these effects were augmented threefold (P Ͻ 0.05), and protein synthesis was increased 34-fold (P Ͻ 0.05). Inferior thoracic vena cava from normoxic or hypoxic rats was unaffected. Norepinephrine-induced growth in hypoxic PA was dose dependent, had efficacy greater than or equal to endothelin-1, required the presence of wall tension, and was inhibited by ␣1A-AR antagonist. In hypoxic pulmonary vasculature, ␣1A-AR was downregulated the least among ␣1-AR subtypes. These data demonstrate that norepinephrine has trophic activity in the PA that is augmented by PH. If evident in vivo in the pulmonary vasculature, adrenergic-induced growth may contribute to the vascular hyperplasia that participates in hypoxic PH. vascular smooth muscle; hypertrophy; catecholamines; adrenergic receptors; hypoxia CHRONIC OBSTRUCTIVE DISEASES, hypoventilatory disorders, and extended exposure to high altitude lead to hypoxic pulmonary hypertension (PH), the most common type of PH not arising from left ventricular dysfunction. Chronic alveolar hypoxia is thought to cause hypoxic-metabolic and/or hemodynamic "injury" to the endothelium and vascular wall, including enhanced production of reactive oxidative species (for a review, see Refs. 6,14,19,33,36,37,and 40). Induction of multiple intracellular and autocrine and paracrine signals leads to proliferation of endothelial cells, vascular smooth muscle cells (VSMCs), fibroblasts, intermediate cells, and pericytes. Proliferation, migration, and matrix accumulation elicit wall hypertrophy, fibrosis, and distal muscularization in the pulmonary arterial circulation. These changes cause structural lumen loss, enhanced VSMC tone, and reduced compliance, which, together with polycythemia, increase pulmonary vascular resistance, right heart hypertrophy, and risk of right heart failure....

α1-Adrenoceptor-dependent vascular hypertrophy and remodeling in murine hypoxic pulmonary hypertension

“…In support of this hypothesis, we recently found that NE stimulates ␣ 1 -AR-dependent growth of the rat pulmonary artery maintained in organ culture (12). Furthermore, this effect was significantly augmented in pulmonary arteries obtained from animals with hypoxic PH.…”

“…Besides growth factor receptor tyrosine kinases, e.g., BMP receptor 2, angiopoietin/Tie2, PDGF␤ receptor, and heparinbinding-EGF/EGF receptor (ErbB1), several G protein-coupled receptor ligands with trophic activity have also been implicated in PH, including serotonin and its transporter and endothelin-1 (7,17,21,22,26,27,33). Catecholamines have also been proposed to contribute to PH (12,29,31,32). Stimulation of certain ␣ 1 -adrenoceptor (␣ 1 -AR) subtypes by norepinephrine (NE) induces growth of VSMCs and adventitial fibroblasts (discussed below).…”

Cervical Ganglion Block Attenuates the Progression of Pulmonary Hypertension via Nitric Oxide and Arginase Pathways

“…10,12,15,21 NO is the primary mediator of vasodilation that is released from the vascular endothelium. …”

“…10,12,15,21 NO is the primary mediator of vasodilation that is released from the vascular endothelium. NO released toward the vascular lumen is a potent inhibitor of platelet aggregation 22 and exerts anti-inflammatory effects by inhibiting leukocyte adhesion to the vessel wall.…”

Comparison of Combination Therapy of Olmesartan plus Azelnidipine or Hydrochlorothiazide on Renal and Vascular Damage in SHR/NDmcr-cp Rats

“…Ishimitsu et al [35] demonstrated in a clinical study that Olm combined with Azl suppressed heart rate, inflammation, and oxidative stress. Meanwhile, catecholamines directly increase NAD(P)H oxidase activity by stimulating ␣ 1 -and ␤ 2 -receptors [36,37] . ␤ 1 -Receptor antagonists improve endothelial function and reduce vascular oxidative stress by NAD(P)H oxidase [38] .…”