Modulation of soluble guanylate cyclase ameliorates pulmonary hypertension in a rat model of chronic thromboembolic pulmonary hypertension by stimulating angiogenesis.
John ZagorskiEvandro Neto-NevesNathan J AlvesAmanda J FisherJeffrey A KlinePublished in: Physiological reports (2022)
Acute pulmonary embolism (PE) does not always resolve after treatment and can progress to chronic thromboembolic disease (CTED) or the more severe chronic thromboembolic pulmonary hypertension (CTEPH). The mechanisms surrounding the likelihood of PE resolution or progress to CTED/CTEPH remain largely unknown. We have developed a rat model of CTEPH that closely resembles the human disease in terms of hemodynamics and cardiac manifestations. Embolization of rats with polystyrene microspheres followed by suppression of angiogenesis with the inhibitor of vascular endothelial growth factor receptor 2 (VEGF-R2) SU5416 results in transient, acute pulmonary hypertension that progresses into chronic PE with PH with sustained right ventricular systolic pressures exceeding 70 mmHg (chronic pulmonary embolism [CPE] model). This model is similar to the widely utilized hypoxia/SU5416 model with the exception that the "first hit" is PE. Rats with CPE have impaired right heart function characterized by reduced VO 2 Max, reduced cardiac output, and increased Fulton index. None of these metrics are adversely affected by PE alone. Contrast-mediated CT imaging of lungs from rats with PE minus SU5416 show large increases in pulmonary vascular volume, presumably due to an angiogenic response to acute PE/PH. Co-treatment with SU5416 suppresses angiogenesis and produces the CTEPH-like phenotype. We report here that treatment of CPE rats with agonists for soluble guanylate cyclase, a source of cGMP which is in turn a signal for angiogenesis, markedly increases angiogenesis in lungs, and ameliorates the cardiac deficiencies in the CPE model. These results have implications for future development of therapies for human CTEPH.
Keyphrases
- endothelial cells
- vascular endothelial growth factor
- pulmonary hypertension
- pulmonary embolism
- drug induced
- pulmonary artery
- left ventricular
- liver failure
- pulmonary arterial hypertension
- inferior vena cava
- heart failure
- respiratory failure
- blood pressure
- atrial fibrillation
- wound healing
- mouse model
- computed tomography
- hepatitis b virus
- protein kinase
- mass spectrometry
- magnetic resonance imaging
- aortic dissection
- photodynamic therapy
- coronary artery
- blood brain barrier
- replacement therapy
- pluripotent stem cells
- acute respiratory distress syndrome
- cerebral ischemia
- dual energy