Serum Response Factor Is Required for Sprouting Angiogenesis and Vascular Integrity

Abstract

Serum response factor (SRF) is a transcription factor that controls the expression of cytoskeletal proteins and immediate early genes in different cell types. Here, we found that SRF expression is restricted to endothelial cells (ECs) of small vessels such as capillaries in the mouse embryo. EC-specific Srf deletion led to aneurysms and hemorrhages from 11.5 days of mouse development (E11.5) and lethality at E14.5. Mutant embryos presented a reduced capillary density and defects in EC migration, with fewer numbers of filopodia in tip cells and ECs showing defects in actin polymerization and intercellular junctions. We show that SRF is essential for the expression of VE-cadherin and beta-actin in ECs both in vivo and in vitro. Moreover, knockdown of SRF in ECs impaired VEGF- and FGF-induced in vitro angiogenesis. Taken together, our results demonstrate that SRF plays an important role in sprouting angiogenesis and small vessel integrity in the mouse embryo.

Role of serum response factor in the pathogenesis of disease

“…46,47 EC-specific inactivation of SRF with a Tie1-Cre mouse resulted in embryonic vascular aneurysms and hemorrhaging of the forebrain and limb buds beginning at e11.5 of development; there was no such phenotype in the blood vessels of the yolk sac vasculature. 48 By contrast, Tie2-Cre-mediated loss of EC SRF led to disruptions in the embryonic and yolk sac blood vessels. 49 Despite differences in phenotype, both EC-specific SRF knockouts resulted in embryonic death at e14.5 of development.…”

“…Moreover, both knockouts reported a disruption in inter-EC junctional complexes with reduced expression of principal junctional proteins such as E-cadherin 49 and vascular endothelial (VE) cadherin, and zona occludens. 48 Importantly, the mouse VEcadherin promoter was shown to contain functional CArG elements that bind to SRF in a ChIP assay and direct CArGdependent promoter activity in vitro. 48 Whether other EC intercellular complex genes are direct targets of SRF remains an open question.…”

“…48 Importantly, the mouse VEcadherin promoter was shown to contain functional CArG elements that bind to SRF in a ChIP assay and direct CArGdependent promoter activity in vitro. 48 Whether other EC intercellular complex genes are direct targets of SRF remains an open question. Another phenotype associated with loss of SRF in ECs was the disruption of the actin cytoskeleton in the so-called tip cells, 48 which give rise to sprouting ECs during angiogenesis.…”

“…48 Whether other EC intercellular complex genes are direct targets of SRF remains an open question. Another phenotype associated with loss of SRF in ECs was the disruption of the actin cytoskeleton in the so-called tip cells, 48 which give rise to sprouting ECs during angiogenesis. 47 This resulted in defective angiogenic sprouting and expansion of subjacent stalk cells, which could underlie the aneurysm phenotype.…”

“…47 This resulted in defective angiogenic sprouting and expansion of subjacent stalk cells, which could underlie the aneurysm phenotype. 48 It will be informative to delete SRF in adult ECs to further illuminate the role of this transcription factor in postnatal angiogenic responses.…”