Researchers have discovered an ingredient vital for proper blood vessel formation that explains why numerous promising treatments have failed. Until now, scientists seeking to grow blood vessels have focused almost exclusively on growing only the inner layer of blood vessels, which are made up of endothelial cells. The hope was that these endothelial cells would then recruit any other cell types needed to form a complete, functional blood vessel.
But researchers have determined that those vessels can develop properly only if they're grown in conjunction with another cell type, known as perivascular cells, including smooth muscle cells and pericytes. The researchers liken these perivascular cells to the outer support layers of a rubber hose or on automobile tires, without which they burst or leak.
By bringing those two models together, the researchers were able to determine the vital role of the perivascular cells in blood vessel formation and to identify a gene, Oct4, that is required for this process. Previously, Oct4 had been thought to be active only in embryonic stem cells during early development and to be permanently inactivated in adult organisms. This belief persisted until two years ago, when the lab showed it was reactivated within smooth muscle cells during formation of atherosclerotic plaques inside blood vessels and required for formation of a protective fibrous cap on those lesions that prevents them from rupturing and setting off a heart attack or stroke - analogous to a patch on a tire. Now the lab has shown that Oct4 has an important role in the formation of the vessels themselves - ironically, being required for forming the protective outer wall of blood vessels.
Using Kelly-Goss' model, the researchers were able to examine blood vessel formation in real time. They found that vessels that lacked perivascular cell coverage formed incompletely and leaked blood. "Multiple failed trials assumed the perivascular cells were just passive followers," the author explained. But without them, the author said, "the whole process comes to a halt." Importantly, they found that endothelial cells and perivascular cells communicate with one another via Oct4-dependent processes and, without it, functional non-leaky blood vessels or blood vessel networks cannot form.
Knockout of Oct4 in perivascular cells significantly impairs perivascular cell migration, increases perivascular cell death, delays endothelial cell migration, and promotes vascular leakage following corneal angiogenic stimulus. Knockout of Oct4 in perivascular cells also impairs perfusion recovery and decreases angiogenesis following hindlimb ischemia.
Transcriptomic analyses demonstrate that expression of the migratory gene Slit3 is reduced following loss of Oct4 in cultured SMCs, and in Oct4-deficient perivascular cells in ischemic hindlimb muscle. Together, these results provide evidence that Oct4 plays an essential role within perivascular cells in injury- and hypoxia-induced angiogenesis.
Stem cell factors role in the growth of blood vessels
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