Intussusceptive-like angiogenesis in human fetal lung xenografts: Link with bronchopulmonary dysplasia-associated microvascular dysangiogenesis?
BACKGROUND
Human fetal lung xenografts display an unusual pattern of non-sprouting, plexus-forming angiogenesis that is reminiscent of the dysmorphic angioarchitecture described in bronchopulmonary dysplasia (BPD). The aim of this study was to determine the clinicopathological correlates, growth characteristics and molecular regulation of this aberrant form of graft angiogenesis.


METHODS
Fetal lung xenografts, derived from 12 previable fetuses (15 to 22 weeks' gestation) and engrafted in the renal subcapsular space of SCID-beige mice, were analyzed 4 weeks posttransplantation for morphology, vascularization, proliferative activity and gene expression.


RESULTS
Focal plexus-forming angiogenesis (PFA) was observed in 60/230 (26%) of xenografts. PFA was characterized by a complex network of tortuous nonsprouting vascular structures with low endothelial proliferative activity, suggestive of intussusceptive-type angiogenesis. There was no correlation between the occurrence of PFA and gestational age or time interval between delivery and engraftment. PFA was preferentially localized in the relatively hypoxic central subcapsular area. Microarray analysis suggested altered expression of 15 genes in graft regions with PFA, of which 7 are known angiogenic/lymphangiogenic regulators and 5 are known hypoxia-inducible genes. qRT-PCR analysis confirmed significant upregulation of SULF2, IGF2, and HMOX1 in graft regions with PFA.


CONCLUSIONS
These observations in human fetal lungs ex vivo suggest that postcanalicular lungs can switch from sprouting angiogenesis to an aberrant intussusceptive-type of angiogenesis that is highly reminiscent of BPD-associated dysangiogenesis. While circumstantial evidence suggests hypoxia may be implicated, the exact triggering mechanisms, molecular regulation and clinical implications of this angiogenic switch in preterm lungs in vivo remain to be determined.
a Department of Pathology and Laboratory Medicine, Alpert Medical School of Brown University , Providence , Rhode Island , USA.|b Department of Pathology, Women and Infants Hospital , Providence , Rhode Island , USA.
Monique E
ME
De Paepe
b Department of Pathology, Women and Infants Hospital , Providence , Rhode Island , USA.
Sharon
S
Chu
a Department of Pathology and Laboratory Medicine, Alpert Medical School of Brown University , Providence , Rhode Island , USA.
Susan J
SJ
Hall
a Department of Pathology and Laboratory Medicine, Alpert Medical School of Brown University , Providence , Rhode Island , USA.
Elizabeth
E
McDonnell-Clark
a Department of Pathology and Laboratory Medicine, Alpert Medical School of Brown University , Providence , Rhode Island , USA.
Nicholas E
NE
Heger
c Department of Molecular Biology, Cell Biology and Biochemistry, Alpert Medical School of Brown University , Providence , Rhode Island , USA.
Christoph
C
Schorl
a Department of Pathology and Laboratory Medicine, Alpert Medical School of Brown University , Providence , Rhode Island , USA.|b Department of Pathology, Women and Infants Hospital , Providence , Rhode Island , USA.
Quanfu
Q
Mao
a Department of Pathology and Laboratory Medicine, Alpert Medical School of Brown University , Providence , Rhode Island , USA.
Kim
K
Boekelheide
D000818:Animals; D000951:Antigens, Neoplasm / Q000378:metabolism; D001997:Bronchopulmonary Dysplasia / Q000209:etiology* / Q000235:genetics / Q000473:pathology*; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases / Q000378:metabolism; D005260:Female; D016332:Fetal Tissue Transplantation / Q000009:adverse effects*; D015870:Gene Expression; D064593:Heterografts; D006801:Humans; D008168:Lung / Q000098:blood supply / Q000378:metabolism / Q000473:pathology; D016040:Lung Transplantation / Q000009:adverse effects*; D008297:Male; D051379:Mice; D016513:Mice, SCID; D055806:Microvessels / Q000378:metabolism / Q000473:pathology*; D009389:Neovascularization, Pathologic / Q000235:genetics
D000951:Antigens, Neoplasm; C089226:CA9 protein, human; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases
BPD; angiogenesis; chronic lung disease of newborn; heme oxygenase 1; insulin-like growth factor; sulfatase 2