Regulation of Pulmonary Circulation

Introduction

Throughout fetal life, the pulmonary circulation forms and establishes a hierarchical system that is essential for postnatal gas exchange. In humans, a continuity of the circulation between the heart and the capillary plexus of the lung appears at approximately 34 days of gestation. ^, There is no appreciable reactivity of pulmonary vessels at midterm gestation, but reactivity increases with advancing gestation thereafter, with increased pulmonary vascular resistance (PVR) and low pulmonary blood flow (PBF). ^, At birth, with the onset of breathing, PVR dramatically decreases and PBF increases to allow the entire right ventricular output to go into the lungs. ^, After birth, the pulmonary vasculature continues to grow in parallel with the growth of the airways to increase gas exchange capacity, making it compatible with somatic growth. ^, During the fetal and neonatal period, regulation of the pulmonary circulation—in comparison with that of adults—is more dynamic, complicated, and vulnerable to injury. In this chapter, regulation of pulmonary circulation of the fetus in utero, at birth, and in the neonatal period is discussed, with a focus on the role of endothelium-derived nitric oxide (NO) and endothelin-1 (ET-1), two key regulators during these periods. ^{, ,} In addition, perinatal mechanisms underlying vascular remodeling and exaggerated vasocontractility, the hallmarks of pulmonary arterial hypertension (PAH), are also discussed.

Development of the Pulmonary Vasculature

Lung development is divided into five distinct histologic stages: embryonic, pseudoglandular, canalicular, saccular, and alveolar. These overlap due to the nonsynchronous development of the lung. During the embryonic stage (4 to 7 postconception weeks [pcw] in humans), the lung bud lined by epithelium first appears as a ventral diverticulum of the foregut at 4 pcw. A continuity of the circulation between the heart and the capillary plexus of the lung exists from at least 5 pcw, with the artery extending from the outflow tract of the heart and the veins connecting to the prospective left atrium. A capillary plexus in the mesenchyme forms between these arteries and veins. ^{, ,} During the pseudoglandular stage (5 to 17 pcw in humans), preacinar airway and vascular structures are formed and all preacinar pulmonary and bronchial arteries are in place, corresponding with the bronchial branching pattern. The canalicular stage (16 to 26 pcw in humans) marks a great increase in the number of lung capillaries in close apposition to the epithelium to form the first air–blood barrier, which is sufficient to sustain life in extremely premature infants. During the saccular stage (24 to 38 pcw in humans), the last generations of airways are formed, which end in clusters of thin-walled saccules. Capillaries form a bilayer within the cellular intersaccular septa. In the alveolar stage, starting at 36 pcw, the interalveolar septa are thinned, the double capillary layer matures into a single-layer adult form, and the microvasculature undergoes marked growth and development. At birth, about one-third to one-half of the adult number of alveoli are present. After birth there is further multiplication of alveoli and the adult number is reached by 3 years of age. The size and surface area of the alveoli increase until the end of adolescence. ^{, , ,}

Regulation of the Pulmonary Circulation in the Perinatal Period