Aberrant Pulmonary Vascular Growth and Remodeling in Bronchopulmonary Dysplasia

Abstract

In contrast to many other organs, a significant portion of lung development occurs after birth during alveolarization, thus rendering the lung highly susceptible to injuries that may disrupt this developmental process. Premature birth heightens this susceptibility, with many premature infants developing the chronic lung disease, bronchopulmonary dysplasia (BPD), a disease characterized by arrested alveolarization. Over the past decade, tremendous progress has been made in the elucidation of mechanisms that promote postnatal lung development, including extensive data suggesting that impaired pulmonary angiogenesis contributes to the pathogenesis of BPD. Moreover, in addition to impaired vascular growth, patients with BPD also frequently demonstrate alterations in pulmonary vascular remodeling and tone, increasing the risk for persistent hypoxemia and the development of pulmonary hypertension. In this review, an overview of normal lung development will be presented, and the pathologic features of arrested development observed in BPD will be described, with a specific emphasis on the pulmonary vascular abnormalities. Key pathways that promote normal pulmonary vascular development will be reviewed, and the experimental and clinical evidence demonstrating alterations of these essential pathways in BPD summarized.

Keywords: HIF; VEGF; alveolarization; chronic lung disease; nitric oxide; pulmonary angiogenesis; pulmonary hypertension.

Figure 1

The interplay of pathologic and clinical factors that lead to pulmonary hypertension in bronchopulmonary dysplasia. Dysmorphic vascular development as a result of altered angiogenic signaling combines with impairments in secondary septation, leading to the development of BPD. These events set the stage, pre- and postnatally, for the development of pulmonary hypertension. The decrease in gas exchange surface area resulting from the impaired secondary septation also sets up a vicious cycle of hypoxemia and dead space ventilation that prolongs the need for mechanical ventilation and oxygen therapy, and induces pathologic changes in pulmonary vascular remodeling and tone, further increasing the risk of pulmonary hypertension.