Current Overview of the Biology and Pharmacology in Sugen/Hypoxia-Induced Pulmonary Hypertension in Rats

Abstract

The Sugen 5416/hypoxia (Su/Hx) rat model of pulmonary arterial hypertension (PAH) demonstrates most of the distinguishing features of PAH in humans, including increased wall thickness and obstruction of the small pulmonary arteries along with plexiform lesion formation. Recently, significant advancement has been made describing the epidemiology, genomics, biochemistry, physiology, and pharmacology in Su/Hx challenge in rats. For example, there are differences in the overall reactivity to Su/Hx challenge in different rat strains and only female rats respond to estrogen treatments. These conditions are also encountered in human subjects with PAH. Also, there is a good translation in both the biochemical and metabolic pathways in the pulmonary vasculature and right heart between Su/Hx rats and humans, particularly during the transition from the adaptive to the nonadaptive phase of right heart failure. Noninvasive techniques such as echocardiography and magnetic resonance imaging have recently been used to evaluate the progression of the pulmonary vascular and cardiac hemodynamics, which are important parameters to monitor the efficacy of drug treatment over time. From a pharmacological perspective, most of the compounds approved clinically for the treatment of PAH are efficacious in Su/Hx rats. Several compounds that show efficacy in Su/Hx rats have advanced into phase II/phase III studies in humans with positive results. Results from these drug trials, if successful, will provide additional treatment options for patients with PAH and will also further validate the excellent translation that currently exists between Su/Hx rats and the human PAH condition.

Keywords: PAH pathogenesis; Sugen 5416/hypoxia rat model; current and novel therapies for PAH; pulmonary arterial pressure (PAH); translation between the Su/Hx rat model and human PAH.

FIG. 1.

Hallmarks of pulmonary arterial hypertension (PAH) and current/emerging therapies. The initial key pathological manifestations of PAH are endothelial dysfunction and excessive proliferation of the pulmonary vascular smooth muscle and endothelial cells that lead to vasoconstriction, vascular inflammation, intimal and adventitial fibrosis, vascular remodeling with hypertrophy/hyperplasia, neointima formation, and plexiform lesions. Also, imbalances between the production of vasodilator (nitric oxide [NO] and prostacyclin) and vasoconstrictor (endothelin-1 and angiotensin) mediators contribute to the emergence of PAH. Current therapies (1) act through the three main pathways regulating the vascular tone: prostacyclin analogs (epoprostenol, treprostinil, and iloprost) or prostacyclin receptor agonist (selexipag), NO pathway (PDE5 inhibitors sildenafil and tadalafil) or guanylate cyclase stimulator (riociguat), and endothelin receptor antagonists (bosentan, ambrisentan, and macitentan). However, because of the limited effects of current therapies and with the multiple mechanisms underlying the PAH pathogenesis, new drugs targeting various pathological pathways (2) have emerged and have been tested in the Sugen/hypoxia rat model.

FIG. 2.

(A) Time course changes in right ventricular systolic pressure (RVSP) in rats exposed to hypoxia (Hx, 3 weeks) and normoxia (Nx, 5 weeks) at 1, 2, 3, 5, 6, 7, and 8 weeks after the Sugen5416 injection. Values are mean ± SE (n = 4). *A p value of ≤0.05 versus Day 0 (one-way analysis of variance with Dunnett’s multiple comparisons test). (B) Representative lung photomicrograph (20× magnification) with α-smooth muscle actin (α-SMA) antibody stain to target pulmonary smooth muscle cells at Day 0 (control), Day 22 (return to Nx after 3 weeks of Hx), and at Day 56 (last day of the study) in the 8-week rat Sugen 5416/hypoxia (Su/Hx) study. Red arrows indicate increased muscularization of small arteries after Su/Hx challenge (Day 22 and Day 56), and black arrows reveal normal thin muscular small arteries (before Su/Hx challenge at Day 0) in lung tissues immunohistochemically stained with α-SMA antibody. Scale bar = 200 µm. (C) Representative lung photomicrograph (20× magnification) with von Willebrand factor (vWF) stain to target pulmonary endothelial cells at Day 0 (control), Day 22 (return to Nx after 3 weeks of Hx), and Day 56 (last day of the study) in the 8-week rat Su/Hx study. Staining with vWF demonstrates increased endothelial cell proliferation as shown by the thickening of the pulmonary arteries (red arrows) (Day 56). Black arrows indicate normal or reduced endothelial cell proliferation (Day 0). Scale bar = 200 µm. At Day 22 (return to Nx), the RVSP slightly drops but remains elevated due to pulmonary arterial smooth muscle cell remodeling induced by 3 weeks of Hx. The following weeks (weeks 3–8) show stable increase of the RVSP, which is associated with endothelial cell proliferation within the small pulmonary arteries and the formation of plexiform lesions (personal communication, Dan Salvail, IPS Therapeutique Inc., Sherbrooke, QC, Canada).