Intussusceptive-like angiogenesis in human fetal lung xenografts: Link with bronchopulmonary dysplasia-associated microvascular dysangiogenesis?

Abstract

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 post-transplantation 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 non-sprouting 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. Conclusion 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.

Remodeling of the Microvasculature: May the Blood Flow Be With You

“…Although altered capillary pruning has been described in tumors ( Holash et al, 1999 ), it may also occur in ischemic disorders as myocardial infarction ( Luttun et al, 2002 ; Gkontra et al, 2019 ), hypertension ( Boudier, 1999 ), and age-related neurodegeneration or Alzheimer’s disease ( Wu et al, 2005 ; Bell and Zlokovic, 2009 ; Sagare et al, 2012 ) exacerbating the hypo-perfusion of the damaged tissue. Capillary splitting has been observed among others in inflammatory bowel disease ( Mori et al, 2005 ; Ravnic et al, 2007 ; Esteban et al, 2020 ), tumors ( Patan et al, 1996b ; Ribatti and Djonov, 2012 ), lung dysplasia of prematurity ( De Paepe et al, 2015 , 2017 ) and other syndromes ( Giacomini et al, 2015 ) contributing to disease progression. Impaired endothelial cell responses involved in microvascular remodeling can also result in the persistence or arteriovenous shunts, the basis for arteriovenous malformations (AVM) ( Red-Horse and Siekmann, 2019 ).…”

A Pathogenic Relationship of Bronchopulmonary Dysplasia and Retinopathy of Prematurity? A Review of Angiogenic Mediators in Both Diseases

“…These studies demonstrate that in both BPD and ROP the ratio of Ang1 to Ang2 favors the anti-angiogenic Ang2; this imbalance may contribute to abnormal vessel formation in both the lung and the eye. While this abnormal vessel development cannot be documented within the living human lung, the work by DePaepe et al suggests that like the immature retina, the lung also undergoes abnormal, and attenuated vessel formation after preterm birth ( 57 ).…”

Investigating the influence of mtDNA and nuclear encoded mitochondrial variants on high intensity interval training outcomes

“…The FAM185A gene has to date had limited previous research and as such we were unable to elucidate any specific molecular function within the context of exercise training. However, the gene has been previously associated with plexus-forming angiogenesis within the context of foetal lung tissue 36 . It is plausible that the gene is involved in angiogenic processes outside embryonic development.…”