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The Role of Perivascular Edema and Endothelial Barrier Function in Pulmonary Arterial Hypertension

Ruslan Rafikov

Anup Srivastava

Ankit Desai

Marc Simon

Olga Rafikova


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Conference: 2018 PHA International PH Conference & Scientific Sessions

Release Date: 07.28.2018

Presentation Type: Abstracts

File Download: Conference 2018_100711

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2018 International PH Conference and Scientific SeAbstract presented at the 2018 International PH Conference and Scientific Sessions in Orlando, Fla., June 28-July 1, 2018.


Pulmonary arterial hypertension (PAH) is a progressive condition, characterized by a continued increase in pulmonary pressure that ultimately leads to right heart failure and death. Although PAH is a rare disease with 10-15 cases per million for the general population (0.001%), patients with hemolytic anemias have a high frequency of PAH development of up to 80%. While the association between sickle cell disease (SCD), thalassemia and the risk of PAH development is well-established, other hemolytic conditions such as G6PD deficiency, spherocytosis and microangiopathic hemolytic anemia (MAHA) were also shown to be associated with PAH. Thus, chronic hemolytic conditions contribute significantly to PAH risk, but mechanisms hemolysis involvement in PAH development remain unclear. Apart from the ability of hemoglobin (Hb) to scavenge nitric oxide and to produce reactive oxygen species in circulation, no additional mechanistic studies exist on the role of free hemoglobin involvement in PAH.


Plasma samples from patients with and without pulmonary arterial hypertension (both confirmed by right heart catheterization) were used to measure free Hb and its correlation with the severity of PAH. A sugen (50mg/kg) /hypoxia (3wks) /normoxia (2wks) and monocrotaline (60mg/kg) 2wks rat models were used to elucidate the role of free Hb/heme pathways in PAH. Human lung microvascular endothelial cells (HLMVECs) were utilized to study heme-mediated endothelial barrier effects.


Our data indicate that PAH patients have significantly, 5-fold, elevated free hemoglobin in plasma. Further analysis of clinical data indicated a strong correlation (r=0.78, p<0.0001) between levels of hemolysis and mean Pulmonary Arterial Pressure (mPAP). We also found a significant correlation (r=0.58, p<0.0003) between free Hb and Pulmonary Vascular Resistance (PVR). Free Hb also negatively correlated with Cardiac Index (CI) (r= -0.42, p<0.01). Using cell culture model we found that, in contrast to free Hb, its degradation product - free heme, induces intracellular pathways in endothelial cells (EC) leading to PAH development. We observed that free heme activates the p38/HSP27 pathway and redistributes tight junction from cell-cell contacts into the perinuclear region leading to EC barrier dysfunction with the formation of perivascular cuffs around pulmonary arteries in the animal model. The main features of perivascular edema such as decreased vaso-reactivity, increased stiffness, inflammatory cells infiltration and local hypoxia around the vessel may all contribute to pathologic vascular remodeling. Interestingly, in both animal PAH models, monocrotaline and Sugen/Hypoxia, we found the formation of perivascular cuffs at the earlier stage of the PAH.


Local hypoxia, stiffness and inflammation in the pulmonary circulation induced by perivascular fluids around vessels can explain remodeling activation and why patients develop PAH without being under hypoxic condition.