Does the Renin-Angiotensin System Participate in Regulation of Human Vasculogenesis and Angiogenesis?

Abstract

Several lines of evidence suggest that hypertension and angiogenesis may be related phenomena but a functional link remains elusive. Here, we propose that the renin-angiotensin system (RAS), in addition to its central role in arterial hypertension, also regulates blood vessel formation during normal development and cancer. This mechanistic hypothesis is based on reports of biochemical, genetic, clinical, and epidemiologic data reviewed herein. Species differences between the RAS of rodents and humans likely account for why such a fundamental role in angiogenesis went unrecognized for so long. If proven correct, this hypothesis carries many implications for the medical practices of cardiology, oncology, and neonatology. [Cancer Res 2008;68(22):9112-5]

Cooperative effects of aminopeptidase N (CD13) expressed by nonmalignant and cancer cells within the tumor microenvironment

“…The only well-defined substrate is angiotensin III in the renin-angiotensin pathway, in which APN cleaves the NH 2 -terminal arginine residue of angiotensin III to form angiotensin IV. Consistent with several lines of evidence, we have previously identified APN as a target for inhibition of tumor vascularization and growth (18)(19)(20).…”

“…The only well-defined substrate is angiotensin III in the renin-angiotensin pathway, in which APN cleaves the NH 2 -terminal arginine residue of angiotensin III to form angiotensin IV. Consistent with several lines of evidence, we have previously identified APN as a target for inhibition of tumor vascularization and growth (18)(19)(20).Tumor growth relies on a complex microenvironment in which malignant cells cooperate with various other cell types: endothelial cells of the blood and lymphatic circulation, mesenchymal stromal cells/cancer-associated fibroblasts, and a variety of bone marrow-derived cells such as myeloid-derived suppressor cells and lymphocytes (21, 22). Some of these cell populations cooperate in inducing desmoplasia and angiogenesis.…”

“…If so, one could speculate that functionally different or site-specific isoforms might be differentially targeted either by ligand motifs [such as asparagine-glycine-arginine (NGR)] (5,18,19) or by certain anti-CD13 monoclonal antibodies (58). Previous studies from our laboratory have demonstrated reduction of tumor growth by targeting an isoform of APN expressed in the tumor vasculature with NGR coupled to doxorubicin in murine models (18)(19)(20). These preclinical studies have been followed with phase II/III clinical trials based on NGR genetically fused to tumor necrosis factor α for the treatment of hepatocarcinomas, pleural mesotheliomas, and colorectal cancer (59)(60)(61)(62)(63)(64).…”

The association between therapeutic outcomes and VEGF G-1154A and C-936T gene polymorphisms in patients with glomerulonephritis

“…1 In rat studies, the pharmacological inhibition of VEGF release from podocytes has led to loss of fenestrae, endotheliosis, loss of podocytes, and proteinuria. 7,20 Khakoo et al 21 have stated that proteinuria leads to an increase in VEGF expression. Ayerder et al 22 have shown that VEGF expression is diminished significantly when blood pressure was normalized by angiotensin converting enzyme inhibitors.…”

Identification of Circulating Natural Antibodies against Endogenous Mediators in the Peripheral Blood Sera of Patients with Osteoarthritis of the Knee: A New Diagnostic Frontier

“…Vasoregulatory systems, as the KKS and the RAS, play essential roles in the maintenance of vascular homeostasis [25,26]. An understanding of the various regulatory systems controlling blood vessel growth, inflammation and pain in the joint should lead to help explain kOA progression.…”