Blood, the river of life, flows through an ever-narrowing,ever-branching stream of arteries and arterioles,capillaries and veins. Non-stop throughout a long or shortlife, it delivers a cargo of oxygen and blood-bornemolecules, returning with a ballast of waste materials enroute to excretion.
Lining the aptly named blood vessels that carry this fluidfreight is a single, ultra-smooth layer of endothelial cells,which fit together seamlessly and tightly, like amortarless brick wall. During gestation, these cellsproliferate to endow the growing embryo and fetus with acomplete pipeline network to channel the blood throughthe body.
Once this job of angiogenesis is done, the endotheliumstops growing. Sometimes, however, a bright red, raisedspot on a newborn baby's skin shows where theendothelial cells overshot their programmed growth, andproduced a "strawberry mark" hemangioma.
Otherwise, endothelia have a built-in knack for resumingproduction later in life, to seal over and renew injuredblood vessels. They also have a propensity, in manydiseases, for forming new vessels where they don'tbelong _ for instance, in tumors, restenosis, arthriticcartilage, psoriasis, glaucoma and diabetic retinopathy.
How do endothelial cells "know" when it's time to divideand multiply, to pave replacement capillaries, veins andarteries? Or to perpetrate untimely, pathogenic,neovascularization? When certain white blood cells,(leukocytes) with neutrophils in the lead, move intoaction and nudge them awake. And there's the rub,literally. It isn't just enough for a neutrophil to rub upagainst an endothelial cell. The two must adhere in orderto trigger angiogenesis.
To launch neovascularization, whether for good (woundhealing) or ill (disease), circulating neutrophils mustadhere to and squeeze through the endothelial cells' tightjunctions. This raises the curtain on an intricate ballet ofcell adhesion molecules (CAM).
Tipped off by an advance party of cytokines, theendothelial cells express a task force of neutrophil-specific CAMs, most of them integrins or selectins. Thecirculating neutrophils, in turn, carry receptors specific tothose CAMs on the vascular endothelia.
Selectins tether the neutrophils briefly to the blood vesselwall. As the on-flowing blood breaks one loose, therolling leukocyte grapples another selectin, to slow itssurfing. Eventually, integrin receptors, expressed by thetumbling neutrophil, tighten its hold sufficiently so it canpenetrate the endothelial interstices, and triggerangiogenesis.
Such, at least, is the story so far, reflecting recentresearch.
That understanding moves another notch forward with anarticle in the current issue of Nature, dated Aug. 9, titled:"Angiogenesis mediated by soluble forms of E-selectinand vascular cell adhesion molecule-1 [VCAM-1]." Itssenior author is Peter Polverini, who heads the laboratoryof molecular pathogenesis at the University of Michiganin Ann Arbor.
Researchers Test Hypothesis
He and his co-authors have chosen rheumatoid arthritis asa site for testing the hypothesis that soluble endothelialadhesion molecules promote angiogenesis.
They report that human recombinant soluble E-selectinand VCAM-1 did indeed generate new blood vessels inthe cornea of rats, a part of the eyeball normally notvascularized. Selectin did so in three out of four corneastested; CAM-1 in all four.
To work this magic on endothelial cells, the teamdetermined that both soluble molecules lured humanendothelial cells in vitro by chemotaxis _ chemicalattraction.
More to the point, monoclonal antibodies to the selectinand CAM-1 blocked both chemotaxis and angiogenesis inrheumatoid synovial fluid _ the joint lubricantimplicated in rheumatoid arthritis.
Rheumatoid synovial fluid produced florid angiogenesisin rat corneas, an effect "diminished or completelyabolished" by anti-selectin and CAM-1 antibodies,Polverini told BioWorld Today.
He and his co-authors also found evidence of cause-and-effect linkage between cellular adhesion andangiogenesis, usually regarded as separate phenomena.The apparent coupler, Polverini explained, is the b3subunit of integrin. "This is expressed in rheumatoidarthritic, angiogenesis-rich synovial tissue, but not innormal tissue," he said.
Trendy Target For Drug Discovery
He and his co-authors are now beginning to investigatealteration in the CAMs involved in angiogenesis ofpsoriasis and tumors. "Once we identify these," heobserved, "we hope to use the soluble endothelialadhesion molecules as pharmacological agents inangiogenesis."
Genentech Inc., of South San Francisco, he added, "isfocusing on anti-angiogenesis therapies withpharmaceutical potential."
Commenting in Nature on the Polverini group's paper,angiogenesis expert Napoleone Ferrara at Genentech'sdepartment of cardiovascular research, observed: "Inrheumatoid arthritis, the new blood vessels play a centralpathogenic role, as they confer on the inflamed synoviumthe ability to proliferate rapidly and destroy the articularcartilage."
However, Ferrara told BioWorld Today: "Rheumatoidarthritis is not the principal target of angiogenesisresearch. Many biotechnology firms," he added, "findangiogenesis an attractive field, and are looking forpotential cures."
Ferrara also remarked that, "We at Genentech wereamong the first to clone vascular endothelial growthfactor," another prime inducer of neovascularization. n
-- David N. Leff Science Editor
(c) 1997 American Health Consultants. All rights reserved.