Neuropilin in Pathological Angiogenesis

Tumor Angiogenesis

Many tumor cell types express NRP1 and NRP2 and bind VEGF165. NRPs are the only VEGF receptors expressed by these tumor cells, so that any VEGF 165 activity must be mediated by NRPs. In several clinical studies, NRP1 and NRP2 expression was correlated with increased aggressiveness, malignancy, and/or hypervascularity. For example, NRP1 was upregulated in primary sporadic prostate tumors at different clinical stages. The correlation between NRP1 overexpression with advanced disease suggested that NRP1 overexpression might be a marker of aggressiveness.

The function of NRP1 in tumor cells has been analyzed directly by expressing NRP1 in tumor cells under the control of a tetracycline-inducible promoter. Concomitant with increased NRP1 expression in response to tetracycline, tumor cell migration and VEGF165 binding was increased. However, induction of NRP1 did not affect tumor cell proliferation. When rats injected with rat prostate carcinoma cells were fed tetracycline, NRP1 synthesis was induced in vivo and tumor size was increased by up to sevenfold, compared to control. The tumors were characterized by markedly increased microvessel density, increased EC proliferation, dilated blood vessels, and notably less tumor cell apoptosis compared to noninduced controls. In addition, tumors overexpressing NRP1 retained higher levels of VEGF, possibly because of "trapping" by NRP1. It was concluded that NRP1 expression results in enlarged tumors associated with substantially enhanced tumor angiogenesis.

On the other hand, sNRP1 is a tumor antagonist. Tumors of rat prostate carcinoma cells overexpressing recombinant sNRPl in vivo were characterized by extensive hemorrhage, damaged vessels, and apoptotic tumor cells. Because sNRPl inhibits 125I-VEGF165 binding to EC and VEGF165-induced tyrosine phosphorylation of VEGFR-2 in EC in vitro, this tumor phenotype may be caused by VEGF165 withdrawal and lack of bioavailability. Withdrawal of VEGF165 from tumors has previously been shown to result in vascular damage, EC apoptosis, hemorrhage, and extensive tumor necrosis.

Vascular Injury and Disease

NRPs are more highly expressed in the developing embryo as compared with the normal adult, but are induced following injury such as ischemia. Several pathologies that are characterized by ischemia-induced angiogenesis have shown NRP1 upregulation. For example, in the adult mouse, NRP1 expression in ischemic brain was significantly upreg-ulated as early as two hours and persisted at least 28 days after focal cerebral ischemia. There was a marked increase in NRP1 expression in EC of cerebral blood vessels at the border and in the core of the ischemic lesion after seven days. These results suggest that upregulation of NRP1 may contribute to neovascular formation in the adult ischemic brain. In another mouse ischemia model system, very little NRP2 expression was observed in normal blood vessels after birth. However, NRP2 expression was induced in newly sprouting blood vessels in response to ischemia in a hind limb model in which the femoral artery was occluded. Increased NRP1 expression was also detected in pathological retinal neovascularization induced by ischemia. In this case, expression of NRP1 and VEGFR-2 was co-localized in the area of neovascularization.

Essentials of Human Physiology

Essentials of Human Physiology

This ebook provides an introductory explanation of the workings of the human body, with an effort to draw connections between the body systems and explain their interdependencies. A framework for the book is homeostasis and how the body maintains balance within each system. This is intended as a first introduction to physiology for a college-level course.

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