Tissue interactions mediate early events in pulmonary vasculogenesis

Abstract

Extensive study has provided considerable insight into the mechanisms governing branching morphogenesis and developmental maturation of the pulmonary epithelium. The process by which the vascular tree arises in the mesodermal mesenchyme of the developing lung, however, is not known. Because normal epithelial branching and differentiation have been shown to be dependent on interactions with the lung mesenchyme, we hypothesized that the developing pulmonary vasculature is dependent on a reciprocal interaction with pulmonary epithelium. In this study we have defined the temporal and spatial expression of flk-1 mRNA, which encodes an endothelial cell-specific vascular endothelial growth factor (VEGF) receptor, in fetal and neonatal rat lung. Flk-1-positive cells were observed in the lung at every prenatal stage from fetal day 11 through birth, demonstrating that vascularization has been initiated as soon as the lung evaginates from the foregut epithelium. The spatial distribution of vascular precursors was distinct and consistent in early lung (fetal days 11-16): clusters of flk-1-positive cells were localized in the mesenchyme closely apposed to the developing epithelium. This spatial relationship between vascular precursors and the developing epithelium suggested that vascular development in the lung may be dependent on interactions between the two tissue types. To investigate this possibility, day-13 distal lung mesenchyme was cultured in the presence and absence of lung epithelium. Lung mesenchyme cultured in the absence of epithelium degenerated significantly, and few flk-1-positive cells were maintained. In contrast, lung mesenchyme recombined with lung epithelium contained abundant flk-1-positive cells, and their spatial distribution mimicked that observed in vivo. These studies provide the first detailed information regarding the temporal and spatial pattern of pulmonary vascularization in early development and suggest that tissue interactions play an important role in growth and maintenance of the developing lung vasculature. Dev Dyn 2000;217:159 -169.

Expression of Hypoxia-Inducible Factors in Normal Human Lung Development

“…The intimate relationship between the pulmonary vasculature and the airways indicates that these 2 systems interact during development. Recent reports have indeed indicated an essential role for vascularization in airway development [2][3][4]21]. In utero pulmonary development occurs in a relatively hypoxic environment, and one of the most potent angiogenic factors, VEGF-A, is actively transcribed under hypoxic conditions.…”

“…Structurally, the airway branches and pulmonary vessels are closely aligned, indicating an intimate interaction during lung development. A vascular network has been shown to be present from the earliest stage of lung development, and pulmonary vascular development seems to be rate-limiting for airway branching [2][3][4][5][6]. The process of vascular development, in particular angiogenesis, is mainly driven by hypoxia.…”

Resident mesenchymal vascular progenitors modulate adaptive angiogenesis and pulmonary remodeling via regulation of canonical Wnt signaling

“…However, this de novo angiogenesis, while reparative in nature, can also become maladaptive if not patterned correctly via remodeling, regression, and pruning 6‐8 . Mesenchymal regulation of pulmonary vasculogenesis and angiogenesis in the distal lung have been well‐characterized during development 9‐11 . Recently, lineage analysis using a lung‐specific enhancer coupled to the mesenchymal restricted transcription factor Tbx4 provided evidence for mesenchymal‐derived angiogenic precursors 12,13 .…”

Unique Aspects of the Developing Lung Circulation: Structural Development and Regulation of Vasomotor Tone

“…VEGF messenger RNA (mRNA) and protein are localized to distal airway epithelial cells and the basement membrane subjacent to the airway epithelial cells. 32 VEGFR-1 and VEGFR-2 mRNA expression increases during normal mouse lung development 33,34 and is localized to the pulmonary endothelial cells closely apposed to the developing epithelium. 35 VEGF 120 , VEGF 164 , and VEGF 188 are present in alveolar type II cells in the developing mouse lung, and their expression peaks during the canalicular stage, when most of the vessel growth occurs in the lung, then decreases until postnatal day 10 (P10), when it increases to levels that are maintained through adulthood.…”