Heterogeneous distribution of soluble guanylate cyclase in the pulmonary vasculature of the fetal lamb

Abstract

Background: Vascular segments in the fetal lung differ anatomically and functionally from one another. At birth, the nitric oxide (NO) pathway plays an integral role in reducing pulmonary vascular resistance through a marked vasodilation. However, the contributions of each vascular segment to this dilation are unclear. We sought to determine the distribution of soluble guanylate cyclase (sGC), the enzyme NO activates to induce vasodilation across the pulmonary vasculature. Methods: Pulmonary airspaces were expanded with freezing compound and the pulmonary arterial tree was infused with barium sulfate gelatin. Soluble guanylate cyclase was localized by immunohistochemistry across the pulmonary vasculature of four near-term fetal lambs and its immuno-reaction product was assessed by a semiquantitative method. The physi-ologic response of fourth-and fifth-generation arteries and veins isolated from age-matched lambs to NO was measured using standard tissue bath techniques. Results: Clear differences in sGC immunostaining were present throughout the pulmonary vasculature: very weak to absent in large arteries accompanying bronchi, but intensely positive for veins. This pronounced staining for sGC in preacinar veins correlated with a 100-fold greater sensitivity to NO in veins compared to arteries of the same generation. The percentage of arteries staining positively approached 100% at the level of respiratory bronchioles and alveoli. Conclusions: These findings suggest that the increased response to NO in preacinar veins compared to that of arteries is in part due to increased sGC within venous vascular smooth muscle. Furthermore, intense staining within distal arteries implies a greater role for NO-mediated vasodila-tion within these segments. Anat. The pulmonary vasculature of the fetus and the newborn is heterogeneous in structure and function. Anatomically, pulmonary arteries of the near-term fetus and newborn are classified or 'landmarked' according to the airway they accompany (Reid, 1984). The walls of large conduit arteries associated with the cartilagenous airways are thick and are composed of multilayered elastic lamellae (Reid, 1979) allowing the vessel to absorb the direct pressure of blood flow coming from the right ventricle. In the resistance segment of the pulmonary arterial tree that accompanies terminal bronchioles, the vessels contain a thick muscular me-dial layer. In the near-term fetus and through infancy, the precapillary arteriolar bed (at the level of respiratory bronchioles and alveoli) is comprised almost entirely of partially muscular or non-muscular vessels. With age, vessels of the precapillary segment become fully muscularized and in the adult extend to the capillary bed. Although pulmonary veins contain fully, partially, and non-muscular segments similar to those of arteries, the structure of veins differs from that of pulmonary arteries (Michel, 1982). At all stages of development, pulmonary veins are less muscular and have a smaller medial thickness than arteries of the

Paracrine role of soluble guanylate cyclase and type III nitric oxide synthase in ovine fetal pulmonary circulation: a double labeling immunohistochemical study

“…Our immunohistochemical results were in general agreement with results by single immunolabeling for NOS-III (Halbower et al 1994) and sGC (a1 subunit) (D'Angelis et al 1998) within pulmonary vasculature of the ovine fetus. Different from their studies, the exact colocalization of these two enzymes showed on the same tissue section by our double immunolabeling technique demonstrated directly anatomic evidence of a paracrine role of these two key enzymes in the NO/cGMP pathway within fetal pulmonary vasculature.…”

Development of fetal vascular responses to endothelin-1 and acetylcholine in the sheep

“…For example, vascular segments in the fetal sheep lung have been shown to differ anatomically and functionally from one another. Immunostaining for soluble guanylate cyclase showed very weak to no staining in large arteries but intense staining in distal arteries, implying a greater role for NO-mediated vasodilation in smaller arteries (11). Because vessels were precontracted with K ϩ depolarization, we are not able to comment on endothelium-derived hyperpolarizing factor-dependent mechanisms.…”

Nitric Oxide in the Pulmonary Vasculature

“…29 Like NOS3, pulmonary sGC expression undergoes dramatic changes during the transition from the fetal lung to the adult lung. sGC is abundant in VSMCs of the pulmonary resistance vessels of fetal and perinatal animals, 30,31 with peak activity in the perinatal period suggesting a role in the acute drop in pulmonary vascular resistance (PVR) after birth. sGC expression and activity decrease in the adult.…”