Vascular Adaptation of the Right Ventricle in Experimental Pulmonary Hypertension

Abstract

Optimal right ventricular (RV) function in pulmonary hypertension (PH) requires structural and functional coupling between the RV cardiomyocyte and its adjacent capillary network. Prior investigations have indicated that RV vascular rarefaction occurs in PH, which could contribute to RV failure by reduced delivery of oxygen or other metabolic substrates. However, it has not been determined if rarefaction results from relative underproliferation in the setting of tissue hypertrophy or from actual loss of vessels. It is also unknown if rarefaction results in inadequate substrate delivery to the RV tissue. In the present study, PH was induced in rats by SU5416-hypoxia-normoxia exposure. The vasculature in the RV free wall was assessed using stereology. Steady-state metabolomics of the RV tissue was performed by mass spectrometry. Complementary studies were performed in hypoxia-exposed mice and rats. Rats with severe PH had evidence of RV failure by decreased cardiac output and systemic hypotension. By stereology, there was significant RV hypertrophy and increased total vascular length in the RV free wall in close proportion, with evidence of vessel proliferation but no evidence of endothelial cell apoptosis. There was a modest increase in the radius of tissue served per vessel, with decreased arterial delivery of metabolic substrates. Metabolomics revealed major metabolic alterations and metabolic reprogramming; however, metabolic substrate delivery was functionally preserved, without evidence of either tissue hypoxia or depletion of key metabolic substrates. Hypoxia-treated rats and mice had similar but milder alterations. There is significant homeostatic vascular adaptation in the right ventricle of rodents with PH.

Metabolic Reprogramming in the Heart and Lung in a Murine Model of Pulmonary Arterial Hypertension

“…The metabolic alterations detected in RV are in line with the alterations recently published by Graham et al ( 48 ) in a very early mouse model of PAH (SU5416+ 1 week of hypoxia). In the RV, these changes are likely induced by ischemia rather than by impaired oxygen sensing ( 36 ).…”

Murine models of sickle cell disease and beta‐thalassemia demonstrate pulmonary hypertension with distinctive features

“…Lung and RV tissue homogenates (10 mg of tissue) were extracted in methanol: acetonitrile: water (5:3:2 v/v/v – at a 10 mg/ml ratio) prior to UHPLC-MS analyses (Vanquish-QExactive, Thermo Fisher), as described previously in the study of metabolic reprogramming in pulmonary hypertension, 31 with a focus on organ metabolism (including lungs 32 and RV 33 ) and related technical notes. 34 …”

Treatment Targets for Right Ventricular Dysfunction in Pulmonary Arterial Hypertension

“…In summary, multiple preclinical PAH models have shown decreased RV vascular density during RV failure ( 110 , 121 , 122 , 123 ). However, a study in Sugen-hypoxia rats challenged those findings, as the authors show that there is actually increased vascular length and volume in the RV, closely proportional to the degree of RV hypertrophy ( 124 ). Moreover, in human PAH, there is also increased total vascular length in the RV compared with controls ( 125 ).…”