Depending on whom you ask, pericytes are either vital vascular regulators that boost blood flow to needy areas of the brain, or mere bystanders that let other cells take on that job. A new study published January 30 in Nature Neuroscience bolsters the evidence for the former. Researchers led by Berislav Zlokovic of the Keck School of Medicine of the University of Southern California, Los Angeles, found that mice with fewer pericytes than normal had diminished blood flow and lower oxygen levels in the brain. As they grew older, the animals also lost neurons and had trouble carrying out normal mouse activities. Pericytes shrink and die in patients with Alzheimer’s disease, and the study supports the idea that the loss of these cells promotes the disease’s pathology. “It makes a direct link between blood flow dysregulation and neuronal degeneration and loss,” Zlokovic told Alzforum.
Blood Vessel Basics. Pericytes make their homes on capillaries, whereas smooth muscle cells reside on thicker vessels. [Courtesy of Costantino Iadecola and Neuron.]
The paper presents a compelling case, in part because it includes a variety of techniques, Gareth Howell of the Jackson Laboratory in Bar Harbor, Maine, told Alzforum. “It’s almost [always] impossible to be definitive, but the number of experiments they did points to a key role of pericytes” in regulating brain blood flow, said Howell, who was not connected to the study. But Jaime Grutzendler of the Yale School of Medicine in New Haven, Connecticut, disagreed. “The study is not designed to determine the precise contributions of the different cell types to blood flow control because the genetic manipulation used is not exclusive to either smooth muscle cells or pericytes,” he wrote to Alzforum.
When a neuron in the brain feels hungry for oxygen or nutrients, it orders room service, spurring nearby vessels to deliver more blood. Ensuring that supply meets demand is known as neurovascular coupling. A klatch of interacting cells is involved, including neurons, astrocytes, smooth muscle cells, endothelial cells, and pericytes. Researchers still debate which cells adjust blood flow. Smooth muscle cells, which surround arteries and arterioles, are one candidate (see image). Pericytes that sit on capillaries, which lack smooth muscle cells, are another. Some findings suggest pericytes may open the circulatory taps in the brain by allowing capillaries to relax (Yemisci et al., 2009; Hall et al., 2014). But a 2015 study by Grutzendler and colleagues implicated smooth muscle cells that encircle large arterioles (see Jun 2015 news).
Nailing down the role of pericytes in metering blood flow has taken on added importance with the discovery that these cells deteriorate and die in people with AD and other neurodegenerative illnesses. This attrition could contribute to altered blood flow patterns detected by blood oxygen level-dependent (BOLD) fMRI in patients who have early AD.
With this in mind, co-first authors Kassandra Kisler, Amy Nelson, Sanket Rege, and colleagues tested mice that carry only one copy of the gene that encodes platelet-derived growth factor receptor-β. Pericytes need PDGFRβ for survival. The mice have fewer of the cells, which cover about 25 percent less capillary surface area than they would in normal mice. Overall blood delivery to the cerebrum was down 30 percent in these pericyte-starved mice.
To test how blood flow responds to a stimulus, the researchers gave small electric shocks to one of the mice’s hind legs and then monitored changes in cerebral blood flow using in vivo two-photon laser scanning microscopy. They homed in on the portion of the somatosensory cortex that corresponds to the stimulated leg. Capillaries in the genetically modified mice dilated more slowly, reaching 50 percent peak diameter 6.5 seconds later than did vessels in normal mice. The surge in capillary blood flow that follows the stimulus was also tardy in the mice.
To confirm that individual capillaries behaved differently if they didn’t sport a pericyte, the researchers crossed pericyte-deficient mice with animals that express the pericyte marker NG2-dsRed. They then tested the offspring. After the same stimulus, only capillaries with pericytes on them relaxed, Kisler and colleagues found.
Could changes in other cells account for the capillaries’ responses? Not likely, the scientists concluded. They measured the behavior of arterioles, which are swaddled by smooth muscle cells, and detected no differences between the pericyte-lacking mice and normal animals. Endothelial cells, astrocytes, and microglia were also comparable in the two types of mice.
Kisler and colleagues then asked whether the diminished blood flow led to less oxygen availability in the brain. They found that by several measures, including fluorescence of NADH, neurons in the pericyte-deficient mice were indeed receiving less oxygen.
This hypoxia didn’t seem to faze mice under two months old. Their neurons remained alive and responded normally to stimulation. The young mice burrowed, made nests, and explored new objects placed in their cages just as normal mice did.
By the time the mice were six to eight months old, however, they had begun to pay the price for their pericyte shortage. Leg stimulation evoked weak responses with long latent periods from somatosensory neurons, which had begun dying. The animals scored poorly on all three behavior tests. Cerebrovascular flow had diminished further, with the cerebrum receiving 58 percent less blood than usual.
Even so, Grutzendler remained unconvinced that pericytes on capillaries are directly responsible for local changes in vessel diameter. The criterion for distinguishing arterioles from capillaries—vessel size—was not specific enough, Grutzendler claimed. “Using only size as a criterion doesn’t tell you if a blood vessel is covered by smooth muscle cells or pericytes,” he said. Other researchers have noted that pericytes and smooth muscle cells express some of the same markers, including PDGFRb and NRG2. In addition, the pericyte-deficient mice show other defects, such as leaks in the blood-brain barrier and reductions in microvascular density, that could account for their neural deterioration, said Grutzendler. “That makes it difficult to interpret the data in the context of neurovascular coupling,” he told Alzforum.
But Costantino Iadecola of Weill Cornell Medicine in New York said the paper makes a valuable contribution. “They show that in these mice there is a level of hypoxia that has never been connected to pericytes before,” he told Alzforum. Howell said that by linking blood flow changes to neurodegeneration, the study “adds to the growing weight of evidence that vascular dysfunction is likely to be a major contributor to increased susceptibility to Alzheimer’s disease.” He added that determining what happens to the mice between the ages of two and eight months, when the effects of the blood flow alterations start to show up, could help researchers identify molecular pathways that foster neurodegeneration—and possibly reveal ways to stop it. —Mitch Leslie
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