Sugen–morphine model of pulmonary arterial hypertension

Abstract

Pulmonary arterial hypertension is a fatal disease associated with pulmonary vascular remodeling and right ventricular hypertrophy. Pre-clinical animal models that reproduce the human pulmonary arterial hypertension process and pharmacological response to available therapies are critical for future drug development. The most prevalent animal model reproducing many aspects of angioobliterative forms of pulmonary arterial hypertension is the rat Sugen/hypoxia model in which Sugen, a vascular endothelial growth factor receptor antagonist, primarily causes initiation of endothelial injury and later in the presence of hypoxia promotes proliferation of apoptosis-resistant endothelial cells. We previously demonstrated that exposure of human pulmonary microvascular endothelium to morphine and HIV-proteins results in initial apoptosis followed by increased proliferation. Here, we demonstrate that the double-hit of morphine and Sugen 5416 (Sugen-morphine) in rats leads to the development of pulmonary arterial hypertension with significant medial hypertrophy of pre-acinar pulmonary arteries along with neo-intimal thickening of intra-acinar vessels. In addition, the pulmonary smooth muscle and endothelial cells isolated from Sugen-morphine rats showed hyperproliferation and apoptotic resistance, respectively, in response to serum starvation. Our findings support that the dual hit model of Sugen 5416 and morphine provides another experimental strategy to induce significant pulmonary vascular remodeling and development of severe pulmonary arterial hypertension pathology in rats without exposure to hypoxia.

Animal models of pulmonary hypertension: Getting to the heart of the problem

“…Despite comparable elevations in RVSP, occlusive pulmonary vascular lesion burden and RVH, Fischer rats exposed to SuHx develop rapid RV failure leading to near 100% mortality by 7–8 weeks, whereas SD rats show complete survival up to 13 weeks (Jiang et al, 2016; Suen et al, 2019). The propensity of Sugen to exacerbate experimental PH led to combination with several insults other than hypoxia, including T‐cell deficiency (Taraseviciene‐Stewart et al, 2007), ovalbumin sensitisation (Mizuno et al, 2012), pneumonectomy (Happé et al, 2016) and morphine administration (Agarwal et al, 2020).…”

Impact of human immunodeficiency virus on pulmonary vascular disease

“…The combination of hypoxia and Sugen generated one of the most well-established models of PAH today 231 , 232 . The presence of HIV proteins alone tends to decrease VEGF expression in SIV-infected macaques with pulmonary arteriopathy 84 –and experimental models of PAH may employ combinations of known pulmonary vascular insults like [HIV proteins + morphine] 84 or [Sugen + morphine] 233 , all of which recreate pro-angiogenic signaling as hallmarks of PAH.…”

Experimental animal models of pulmonary hypertension: Development and challenges

“…Ovalbumin immunized male SD rats treated with SU5416 result in severe angio‐obliterative PAH, accompanied by increased IL‐6 expression in the lungs 37 . Besides, a single subcutaneous injection of SU5416 (20 mg/kg) and intraperitoneal injections of morphine (10 mg/kg, daily) for 35 days can induce PAH in male SD rats that is similar to human PAH 38 …”

“…37 Besides, a single subcutaneous injection of SU5416 (20 mg/ kg) and intraperitoneal injections of morphine (10 mg/kg, daily) for 35 days can induce PAH in male SD rats that is similar to human PAH. 38…”