In a quiet corner of developmental biology, a study in Nature asks what a blood vessel really needs in order to exist. Mice were engineered so that some of their vessel-lining cells could no longer hear the body's central growth signal, and rather than fading away, those cells multiplied, jostled with their neighbours, and came to make up a substantial share of vessels in most organs. The finding gently unsettles a long-held belief that VEGF and its receptor VEGFR2 are indispensable to building vessels, and it suggests that living tissue may have an older, quieter route of adaptation, one that
Veins Take Over: Endothelial Cells Lacking VEGFR2 Still Build Functional Blood Vessels in Mice
They did not die out or sit idle. They multiplied.
In a quiet corner of developmental biology, a study in Nature asks what a blood vessel really needs in order to exist. Mice were engineered so that some of their vessel-lining cells could no longer hear the body's central growth signal, and rather than fading away, those cells multiplied, jostled with their neighbours, and came to make up a substantial share of vessels in most organs. The finding gently unsettles a long-held belief that VEGF and its receptor VEGFR2 are indispensable to building vessels, and it suggests that living tissue may have an older, quieter route of adaptation, one that also offers a possible explanation for why anti-VEGF treatments in cancer and ischaemic disease sometimes lose their grip.
In mice engineered so that some of their blood vessel cells could no longer respond to the body's main growth signal, those cells did not die out or sit idle. They multiplied, competed with their normal neighbours, and over time built a substantial share of the vascular network in most organs. The study, published in Nature, cuts against a long-held view of how blood vessels grow.
VEGF and its receptor VEGFR2 have been regarded as essential for endothelial cells to differentiate, proliferate, sprout and survive. When this signalling fails in every cell, vessels fail to form in growing embryos. Anti-VEGF antibodies, widely used in cancer and ischaemic disease, rest on that same logic, which makes reports of vessel resistance to them all the more puzzling.
Using genetic tools that create mosaics of cells lacking VEGFR2, the researchers followed these cells through development. At first they could not sprout, since that process depends heavily on VEGF. But they were steered toward veins, where they grew dominant and became a continuous source of endothelial cells for later waves of growth that do not need VEGF.
Single-cell sequencing revealed a shift toward venous identity and increased production of ligands for VEGFR1 and VEGFR3, which offered only partial help. The decisive factor was NR2F2, the master regulator of venous development: without it, the mutant cells' expansion was sharply reduced. The authors argue that venousization is a genuine route of adaptation to lost VEGF signalling, and the open question now is whether this venous path, and its dependence on NR2F2, can be exploited to overcome resistance to anti-VEGF treatment.
In mice engineered so that some of their blood vessel cells could no longer read the body's main growth signal, those cells did not die out or sit idle. They multiplied, competed with their normal neighbours, and over time built a substantial share of the vascular network in most organs. That is the central finding of a study published in Nature, and it cuts against a long-held view of how blood vessels grow.
The background is well established. Vascular endothelial growth factor, VEGF, and its main receptor, VEGFR2, are regarded as essential for endothelial cells to differentiate, proliferate, sprout and survive. When VEGF-VEGFR2 signalling is compromised in every cell, blood vessels fail to form in growing embryos and tissues. Anti-VEGF antibodies, which block angiogenesis in cancer, wound healing and ischaemic disease, are among the most widely used antibodies in the clinic. Yet resistance of blood vessels to anti-VEGF therapy has been reported.
To see what happens when only some cells lose the receptor, the researchers used two genetic tools, iFlpMosaics and iSuRe-HadCre. These let them create and follow mosaics of endothelial cells lacking VEGFR2, called Vegfr2KO cells, throughout embryonic and postnatal development. The work was done in mice, under protocols approved by animal ethics committees in Madrid, and used a range of genetically modified lines, including a newly generated Vegfr3 floxed allele combined with Vegfr1 and Vegfr2 floxed alleles.
The mutant cells were at a clear disadvantage in one respect. During the first wave of angiogenesis in most tissues, they could not sprout, because that process depends heavily on VEGF and favours the growth and mobilisation of normal cells. But their inability to respond to VEGF steered them toward veins, where they became dominant. Veins, in turn, served as a long-term, continuous source of endothelial cells for later waves of angiogenesis that do not depend on VEGF.
Single-cell RNA sequencing compared cells with acute loss of VEGFR2 against those with long-term loss. It identified both shared and organ-specific mechanisms of adaptation. Among them were marked venousization, meaning the cells took on a venous identity, and increased production of ligands for VEGFR1 and VEGFR3, two related receptors.
Those related receptors helped only in limited ways. VEGFR1 partly compensated for VEGFR2 loss in capillary endothelial cells, while VEGFR3 compensated only in arterial cells. When all three VEGF receptors were lost, venous growth was still not compromised. What did hurt the mutant cells was removing NR2F2, also known as COUP-TFII, the master regulator of venous development. Without it, the expansion of Vegfr2KO cells was significantly reduced.
The authors conclude that venousization is a mechanism of adaptation and resistance to loss of VEGF signalling during angiogenesis. They say the work challenges conventional views of VEGF receptors as essential to angiogenesis and offers insight into why anti-VEGF therapies can fail. The study also included a tumour experiment using Lewis carcinoma cells injected into mice, with tumours examined after 15 days. What to watch next is whether the venous route, and its dependence on NR2F2, can be tested as a way around resistance to anti-VEGF treatment.
Citações Notáveis
Venousization is a mechanism of adaptation and resistance to VEGF signalling loss during angiogenesis.— Study authors, Nature
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