Abstract
Angiogenesis and lymphangiogenesis are key processes during embryogenesis as well as under physiological and pathological conditions. Vascular endothelial growth factor C (VEGFC), the ligand for both VEGFR2 and VEGFR3, is a central lymphangiogenic regulator that also drives angiogenesis. Here, we report that members of the highly conserved BACH (BTB and CNC homology) family of transcription factors regulate VEGFC expression, through direct binding to its promoter. Accordingly, down-regulation of bach2a hinders blood vessel formation and impairs lymphatic sprouting in a Vegfc-dependent manner during zebrafish embryonic development. In contrast, BACH1 overexpression enhances intratumoral blood vessel density and peritumoral lymphatic vessel diameter in ovarian and lung mouse tumor models. The effects on the vascular compartment correlate spatially and temporally with BACH1 transcriptional regulation of VEGFC expression. Altogether, our results uncover a novel role for the BACH/VEGFC signaling axis in lymphatic formation during embryogenesis and cancer, providing a novel potential target for therapeutic interventions.
Highlights
The blood and lymphatic networks are two evolutionarily conserved transport systems that provide complementary functions in the maintenance of tissue homeostasis
Similar phenotypes were detected in vegfc morphants (Fig 2A and B), in line with previous reports demonstrating impaired primordial hindbrain channel (PHBC) formation following the blocking of Vegfcactivated Vegfr3 signaling (Covassin et al, 2006b; Hogan et al, 2009b; Villefranc et al, 2013; Schuermann et al, 2015; Shin et al, 2016)
The results presented here demonstrate that members of the BACH family regulate Vascular endothelial growth factor C (VEGFC) expression, thereby promoting angiogenesis and lymphangiogenesis during zebrafish development and in ovarian and lung mouse tumor models
Summary
The blood and lymphatic networks are two evolutionarily conserved transport systems that provide complementary functions in the maintenance of tissue homeostasis. The formation of new blood and lymphatic vessels is a prerequisite for vertebrate embryonic and postnatal development. As early as mouse embryonic day (E) 7.5, vasculogenesis, the formation of a primitive vascular plexus through proliferation, migration, and differentiation of endothelial cells (ECs), takes place. Later on, this plexus undergoes massive remodeling via angiogenesis, which involves arteriovenous differentiation (Chung & Ferrara, 2011). Reactivation of angiogenesis and lymphangiogenesis, is a hallmark of pathological processes associated with wound healing, myocardial infarction, allograft rejection, chronic inflammation, tumor progression, and malignant cell dissemination (Oliver & Alitalo, 2005; Chung & Ferrara, 2011)
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