Pulmonary vascular development goes awry in congenital lung abnormalities

Abstract

Pulmonary vascular diseases of the newborn comprise a wide range of pathological conditions with developmental abnormalities in the pulmonary vasculature. Clinically, pulmonary arterial hypertension (PH) is characterized by persistent increased resistance of the vasculature and abnormal vascular response. The classification of PH is primarily based on clinical parameters instead of morphology and distinguishes five groups of PH. Congenital lung anomalies, such as alveolar capillary dysplasia (ACD) and PH associated with congenital diaphragmatic hernia (CDH), but also bronchopulmonary dysplasia (BPD), are classified in group three. Clearly, tight and correct regulation of pulmonary vascular development is crucial for normal lung development. Human and animal model systems have increased our knowledge and make it possible to identify and characterize affected pathways and study pivotal genes. Understanding of the normal development of the pulmonary vasculature will give new insights in the origin of the spectrum of rare diseases, such as CDH, ACD, and BPD, which render a significant clinical problem in neonatal intensive care units around the world. In this review, we describe normal pulmonary vascular development, and focus on four diseases of the newborn in which abnormal pulmonary vascular development play a critical role in morbidity and mortality. In the future perspective, we indicate the lines of research that seem to be very promising for elucidating the molecular pathways involved in the origin of congenital pulmonary vascular disease.

Pulmonary vascular development in congenital diaphragmatic hernia

“…This indicates that the structural abnormalities start to develop when the lung is very immature. The pathology of PH is characterised by hypermuscularisation of the midsized and large vessels and neomuscularisation of the small capillaries [18,28,30,31]. Pericytes are prime candidates to underlie and eventually modulate the structural changes observed in PH associated with CDH [6,32].…”

“…Retinoic acid is formed from vitamin A through several sequential enzymatic reactions. Subsequently, it binds to one of the retinoic acid receptors (RAR/RXR) which subsequently modulate transcription of target genes through retinoic acid responsive element [18]. Pharmacological or genetic inactivation of retinoic acid signalling in the early foregut resulted in an increased expression of the Wingless-type MMTV integration site family (Wnt) antagonist Dickkopf (Dkk1) and transforming growth factor (TGF)-β, which plays an important role in airway branching and muscularisation of the pulmonary vasculature [19].…”

Pulmonary hypertension in the premature infant

“…While there are still many questions to answer, it is widely accepted that the pulmonary blood vessels develop alongside the airways and throughout development the lung endoderm and vasculature mesoderm are interacting through molecular pathways (9, 12, 13). Vascular endothelial growth factor (VEGF) is very important for signaling of vascular growth and endothelial cell proliferation (14, 15) and this endothelial cell signaling closely interacts with signaling for lung development.…”

“…A correlation between the diagnosis of BPD and PH is not surprising, given that alveolarization during lung growth requires pulmonary vascular development (8). Consequently, understanding the pathophysiology of PH in the BPD population involves an understanding of the interactions of these two processes as well as how other factors such as inflammation can influence these interactions (9). …”

The Future of Bronchopulmonary Dysplasia: Emerging Pathophysiological Concepts and Potential New Avenues of Treatment

“…Despite the large body of knowledge concerning the morphogenesis of the lung (18, 19), research on the intercellular communications that regulate growth, migration, and differentiation during lung development is still unfolding. Among the best characterized growth factors and their signaling components in early lung development are fibroblast growth factor (FGF), transforming growth factor β (TGFβ), bone morphogenetic protein (BMP), sonic hedgehog (SHH), wingless-type MMTV integration site family (WNT), vascular endothelial growth factor (VEGF), and retinoic acid signaling pathways [reviewed by Hogan and Morrissey (20) and Kool et al (21)]. Far less is known about the molecular and cellular processes that direct saccular and alveolar development, the very stages that are clinically relevant after preterm birth and BPD pathogenesis.…”