Browsing by Author "Frump, Andrea"

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    BMPR2 mutations and endothelial dysfunction in pulmonary arterial hypertension (2017 Grover Conference Series)
    (Sage Journals, 2018-04) Frump, Andrea; Prewitt, Allison; de Caestecker, Mark P.; Medicine, School of Medicine
    Despite the discovery more than 15 years ago that patients with hereditary pulmonary arterial hypertension (HPAH) inherit BMP type 2 receptor ( BMPR2) mutations, it is still unclear how these mutations cause disease. In part, this is attributable to the rarity of HPAH and difficulty obtaining tissue samples from patients with early disease. However, in addition, limitations to the approaches used to study the effects of BMPR2 mutations on the pulmonary vasculature have restricted our ability to determine how individual mutations give rise to progressive pulmonary vascular pathology in HPAH. The importance of understanding the mechanisms by which BMPR2 mutations cause disease in patients with HPAH is underscored by evidence that there is reduced BMPR2 expression in patients with other, more common, non-hereditary form of PAH, and that restoration of BMPR2 expression reverses established disease in experimental models of pulmonary hypertension. In this paper, we focus on the effects on endothelial function. We discuss some of the controversies and challenges that have faced investigators exploring the role of BMPR2 mutations in HPAH, focusing specifically on the effects different BMPR2 mutation have on endothelial function, and whether there are qualitative differences between different BMPR2 mutations. We discuss evidence that BMPR2 signaling regulates a number of responses that may account for endothelial abnormalities in HPAH and summarize limitations of the models that are used to study these effects. Finally, we discuss evidence that BMPR2-dependent effects on endothelial metabolism provides a unifying explanation for the many of the BMPR2 mutation-dependent effects that have been described in patients with HPAH.
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    Neonatal hyperoxic lung injury favorably alters adult right ventricular remodeling response to chronic hypoxia exposure
    (American Physiological Society, 2015-04-15) Goss, Kara N.; Cucci, Anthony R.; Fisher, Amanda J.; Albrecht, Marjorie; Frump, Andrea; Tursunova, Roziya; Gao, Yong; Brown, Mary Beth; Petrache, Irina; Tepper, Robert S.; Ahlfeld, Shawn K.; Lahm, Tim; Department of Medicine, IU School of Medicine
    The development of pulmonary hypertension (PH) requires multiple pulmonary vascular insults, yet the role of early oxygen therapy as an initial pulmonary vascular insult remains poorly defined. Here, we employ a two-hit model of PH, utilizing postnatal hyperoxia followed by adult hypoxia exposure, to evaluate the role of early hyperoxic lung injury in the development of later PH. Sprague-Dawley pups were exposed to 90% oxygen during postnatal days 0-4 or 0-10 or to room air. All pups were then allowed to mature in room air. At 10 wk of age, a subset of rats from each group was exposed to 2 wk of hypoxia (Patm = 362 mmHg). Physiological, structural, and biochemical endpoints were assessed at 12 wk. Prolonged (10 days) postnatal hyperoxia was independently associated with elevated right ventricular (RV) systolic pressure, which worsened after hypoxia exposure later in life. These findings were only partially explained by decreases in lung microvascular density. Surprisingly, postnatal hyperoxia resulted in robust RV hypertrophy and more preserved RV function and exercise capacity following adult hypoxia compared with nonhyperoxic rats. Biochemically, RVs from animals exposed to postnatal hyperoxia and adult hypoxia demonstrated increased capillarization and a switch to a fetal gene pattern, suggesting an RV more adept to handle adult hypoxia following postnatal hyperoxia exposure. We concluded that, despite negative impacts on pulmonary artery pressures, postnatal hyperoxia exposure may render a more adaptive RV phenotype to tolerate late pulmonary vascular insults.
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    Pathophysiology and new advances in pulmonary hypertension
    (BMJ, 2023-03-23) Bousseau, Simon; Fais, Rafael Sobrano; Gu, Sue; Frump, Andrea; Lahm, Tim; Medicine, School of Medicine
    Pulmonary hypertension is a progressive and often fatal cardiopulmonary condition characterised by increased pulmonary arterial pressure, structural changes in the pulmonary circulation, and the formation of vaso-occlusive lesions. These changes lead to increased right ventricular afterload, which often progresses to maladaptive right ventricular remodelling and eventually death. Pulmonary arterial hypertension represents one of the most severe and best studied types of pulmonary hypertension and is consistently targeted by drug treatments. The underlying molecular pathogenesis of pulmonary hypertension is a complex and multifactorial process, but can be characterised by several hallmarks: inflammation, impaired angiogenesis, metabolic alterations, genetic or epigenetic abnormalities, influence of sex and sex hormones, and abnormalities in the right ventricle. Current treatments for pulmonary arterial hypertension and some other types of pulmonary hypertension target pathways involved in the control of pulmonary vascular tone and proliferation; however, these treatments have limited efficacy on patient outcomes. This review describes key features of pulmonary hypertension, discusses current and emerging therapeutic interventions, and points to future directions for research and patient care. Because most progress in the specialty has been made in pulmonary arterial hypertension, this review focuses on this type of pulmonary hypertension. The review highlights key pathophysiological concepts and emerging therapeutic directions, targeting inflammation, cellular metabolism, genetics and epigenetics, sex hormone signalling, bone morphogenetic protein signalling, and inhibition of tyrosine kinase receptors.