New blood vessels in a healing wound arise chiefly by angiogenesis: sprouts grow from surviving blood vessels, unite into patent channels, and mature within the granulation tissue. Blood does not simply excavate permanent channels in a shapeless clot.
The initial wound contains a provisional extracellular matrix, including fibrin, with inflammatory biological cells and later fibroblasts. Local hypoxia and signals from injured tissue and inflammatory biological cells stimulate surviving endothelium. In modern molecular terms, vascular endothelial growth factor is an important stimulus. This molecular account explains the process today; it is not evidence that the examiner expected the named signalling molecule in 1867.[ref]
Molecular Biology of the Cell, 4th edition. Chapter 22, Blood Vessels and Endothelial Cells, Angiogenesis Is Controlled by Factors Released by the Surrounding Tissues; Figure 22-27
- Portions of the old vascular basement membrane and surrounding extracellular matrix are remodelled. Activated endothelium biological cells extend and migrate towards the wound.
- Endothelium cell proliferation and cell migration lengthen the sprouts. Their organization establishes a lumen rather than a solid cord remaining indefinitely.
- Sprouts meet one another or an existing blood vessel, forming an anastomosis. A connected route with inflow and outflow can then carry blood. A blind sprout is not yet a useful circulating loop.
- Junctions between endothelium biological cells, a renewed basement membrane, and supporting pericytes stabilize the small blood vessels. Larger channels acquire further mural support as appropriate.
- During remodelling, many surplus capillaries regress. The vascular, red granulation tissue becomes a less vascular mature scar.
This sequence separates growth of the cellular lining, formation of the channel, establishment of flow, and stabilization. These are different experimental observations, even though they overlap in time.[ref]
Angiogenesis in Inflammation and the Microcirculation. Chapter 6, initiation by endothelial activation, matrix degradation, migration, proliferation and maturation
An instructive anatomical investigation follows the wound at successive stages. Thin sections show solid sprouts, lumina lined by endothelium and their relation to the old blood vessels. Injection of a suitable casting material into the supplying blood vessels, followed by examination of the cast, reveals which channels are continuous with the circulation. The corneal wound example in the modern textbook uses resin injection and scanning electron microscopy of the resulting casts. Seeing an cord of endothelium and demonstrating a perfused loop therefore answer different questions.[ref]
Molecular Biology of the Cell, 4th edition. Chapter 22, Blood Vessels and Endothelial Cells, Figure 22-27 caption, vascular casts after corneal wounding
The essential repair process is sprouting, lumen formation, connection and maturation. The contrast with embryonic vasculogenesis, assembly from vascular precursors, helps define angiogenesis; it does not require assuming that every new blood vessel in an adult wound has an identical cellular history.
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