Temporal and spatial regulation of VEGF-A controls vascular patterning in the embryonic lung

Abstract

Vascular endothelial growth factor-A (VEGF-A) is required for vascular development throughout the embryo and has been proposed to play an important role in pulmonary vascular patterning. Expressed by the embryonic respiratory epithelium, VEGF-A signals endothelial cells within the splanchnic mesenchyme. To refine understanding of the spatial and temporal role of VEGF-A in lung morphogenesis, isoform VEGF164 was expressed under conditional control in distal and proximal airway epithelial cells. Unexpectedly, increased expression of VEGF164 in distal lung disrupted peripheral vascular net assembly and arrested branching of airways tubules without altering endothelial cell proliferation or apoptosis. Peripheral airway branching and vascular smooth muscle patterning were also altered. In contrast, expression of VEGF164 by epithelial cells of the conducting airways caused atypical evaginations of small capillary-like vessels into large airways but did not alter peripheral vascular net assembly or branching morphogenesis. These data demonstrate that the differential response of endothelial cells in distal vascular beds and large central blood vessels is established early in lung development. Precise temporal and spatial expression of VEGF-A is required for vascular patterning during lung morphogenesis. Disruption of pulmonary vascular assembly perturbs reciprocal interactions with epithelium leading to altered airway branching morphogenesis.

Glomerular Structure and Function Require Paracrine, Not Autocrine, VEGF–VEGFR-2 Signaling

“…Generation and characterization were previously described. 29,30 In rosa-rtTA transgenic mice, the coding sequence for reverse tetracycline transactivator (rtTA) was targeted into the ubiquitously expressed ROSA26 locus. Because a floxed STOP codon precedes the coding sequence for rtTA, expression is dependent on a Cre excision.…”

Hyperoxia enhances VEGF release from A549 cells via post-transcriptional processes

“…Coordinated temporal and spatial expression of lung VEGF is crucial for the successful development of endothelial and epithelial cells into functional gas exchange units [23]. Aberrant VEGF expression leads to lung dysmorphogenesis, producing poor septal formation and a generalized emphysematous architecture [24,25].…”

Induction of Podocyte VEGF164 Overexpression at Different Stages of Development Causes Congenital Nephrosis or Steroid-Resistant Nephrotic Syndrome

“…Transgenic mice were genotyped by PCR using reported primers. 8,25,26 Developing mice were induced with doxycycline during embryonic and early postnatal life. To induce podocyte VEGF 164 overexpression during organogenesis, podocin-rtTA: tet-O-VEGF 164 pregnant mice were given doxycycline in the chow from embryonic day 12 (to ensure therapeutic levels by embryonic day 14, the onset of podocin expression) until the pups were born (total n ϭ 55, podocin-rtTA:tet-O-VEGF 164 [TOPO] n ϭ 26, single transgenic n ϭ 29).…”