Pulmonary veins in the normal lung and pulmonary hypertension due to left heart disease

Abstract

Tuder RM. Pulmonary veins in the normal lung and pulmonary hypertension due to left heart disease. Am J Physiol Lung Cell Mol Physiol 305: L725-L736, 2013. First published September 13, 2013 doi:10.1152/ajplung.00186.2013.-Despite the importance of pulmonary veins in normal lung physiology and the pathobiology of pulmonary hypertension with left heart disease (PH-LHD), pulmonary veins remain largely understudied. Difficult to identify histologically, lung venous endothelium or smooth muscle cells display no unique characteristic functional and structural markers that distinguish them from pulmonary arteries. To address these challenges, we undertook a search for unique molecular markers in pulmonary veins. In addition, we addressed the expression pattern of a candidate molecular marker and analyzed the structural pattern of vascular remodeling of pulmonary veins in a rodent model of PH-LHD and in lung tissue of patients with PH-LHD obtained at time of placement on a left ventricular assist device. We detected urokinase plasminogen activator receptor (uPAR) expression preferentially in normal pulmonary veins of mice, rats, and human lungs. Expression of uPAR remained elevated in pulmonary veins of rats with PH-LHD; however, we also detected induction of uPAR expression in remodeled pulmonary arteries. These findings were validated in lungs of patients with PH-LHD. In selected patients with sequential lung biopsy at the time of removal of the left ventricular assist device, we present early data suggesting improvement in pulmonary hemodynamics and venous remodeling, indicating potential regression of venous remodeling in response to assist device treatment. Our data indicate that remodeling of pulmonary veins is an integral part of PH-LHD and that pulmonary veins share some key features present in remodeled yet not normotensive pulmonary arteries. pulmonary hypertension; pulmonary circulation; left heart failure; pulmonary veins; vessel remodeling ALTHOUGH THE ARTERIAL and venous pulmonary circulations form a communicating, integrated vascular system, pulmonary veins are developmentally, physiologically, and structurally distinct from pulmonary arteries. Pulmonary veins develop chronologically after the initial segments of large pulmonary arteries form and are often identifiable in a perpendicular arrangement to that of the pulmonary arteries in the bronchoarterial sheath (5). Pulmonary veins respond physiologically to the vasodilator prostacyclin and to vasoconstrictors, such as platelet activating factor, to a larger extent than that observed with pulmonary arteries (9, 34). These anatomic and physiological distinctions are carried over to the histological level since pulmonary veins lack distinct double internal and external elastic laminae and have only a thin medial muscular layer (as compared with similar diameter arteries) (32). However, this more refined histological distinction does not persist in diseases characterized by pulmonary hypertension (PH), because pulmonary veins become more arterial in appe...

Relevant Issues in the Pathology and Pathobiology of Pulmonary Hypertension

“…Lung samples obtained from patients with LHF placed on a ventricular assist device showed increased pulmonary vein and artery media thickening. Of interest, some patients who improved on the assist device and underwent repeat lung biopsy had a significant improvement of pulmonary vein remodeling (16). The molecular drivers of these processes remain largely unknown.…”

Pulmonary Veno-occlusive Disease and Pulmonary Hypertension in Dogs

“…Recently, the ephrin B4 receptor (EphB4), a developmental venous marker, has been shown to identify pulmonary veins in adult mice 2 . However, this finding is probably not relevant to other species as careful embryologic studies in humans have demonstrated overlap of ephB4 expression between pulmonary veins and arteries and further EphB4 does not appear to be present in the pulmonary veins of the rat suggesting that EphB4 may not be a marker applicable to humans or animal species other than the mouse 5,6 . To address these challenges a study was recently undertaken to search for unique molecular markers in pulmonary veins.…”

“…2a (please refer to Ref. #6 for details). Fluorescent-tagged solutions are perfused retrogradely via the left atrium, allowing visualization independent of location and overall structural characteristics of the pulmonary venous system.…”

“…2). The investigators detected urokinase plasminogen activator receptor (uPAR) expression preferentially in normal pulmonary veins of mice, rats, and human lungs 6 . In control mice, rats, and human lung tissues, uPAR expression could be detected by immunofluorescence, primarily in the media and less so in the intima and was specific to pulmonary veins (Fig.…”

Cardiac Asthma

“…26 Using a rodent model, they examined the lungs in normal animals and those with pulmonary hypertension associated with LHF. A recent study sought to identify specific pulmonary venous abnormalities as they have been understudied to this point.…”