ORIGINAL ARTICLE Expression of vascular endothelial growth factor receptor-1/-2 and nitric oxide in unruptured intracranial aneurysms E. Maderna • E. Corsini • A. Franzini • S. Giombini • B. Pollo • G. Broggi • C. L. Solero • P. Ferroli • G. Messina • C. Marras Received: 14 July 2009 / Accepted: 25 June 2010 / Published online: 16 July 2010 Ó Springer-Verlag 2010 Abstract The biological mechanisms associated with the development and rupture of intracranial aneurysms are not fully understood. To clarify the role of VEGF and the related receptors in the pathophysiology of aneurysm, immunostaining for VEGF, VEGFR1 and VEGFR2 was performed on specimens from six unruptured aneurysms and on two specimens of normal arteries wall as a control. The results were correlated with NO concentration of CSF collected during surgery from 8 patients affected by unruptured aneurysms and in 11 control patients. The immunohistochemical data showed a different pattern of VEGF/VEGFR1/VEGFR2 in aneurysms when compared with control. The results of this preliminary study suggest an imbalance of VEGF, VEGFR1 and VEGFR2, and the interaction of VEGF and NO in the pathophysiology of unruptured aneurysms. Our data support the hypothesis of aneurysm formation associated with a loss of expression of VEGFR1, moderate expression of VEGFR2 and high concentration of nitrate. Keywords Aneurysms Á Nitric oxide Á VEGF Á VEGFR1 Á VEGFR2 Introduction The biological mechanisms associated with the develop- ment and rupture of cerebral aneurysms are not fully understood. Literature data identifies several factors of predisposition, both inherited and acquired; among these, familiar clustering, vasculopathies, arterial hypertension, female gender, increasing age, cigarette and excessive alcohol consumption [9, 12, 20]. A close correlation between aneurysm size and risk of aneurysm rupture is reported [7]. However, intracranial aneurysms are not always associated with the above-mentioned factors, sug- gesting other mechanisms contributing their formation. Cerebral aneurysms are characterized by morphological alterations of arterial wall that may be due to elevated shear stress, injuries or compromised repair mechanisms [12, 15]. Endothelial degenerative changes and abnormal remodeling in vascular wall are also reported [3, 11, 20]. Abnormal angiogenesis might play a role in the devel- opment and rupture of cerebral aneurysms [13]. Skirgaudas et al. [23] also found increased VEGF expression on aneurysms wall. Others studies demonstrated a significant contribution of NO to vascular wall alteration in animal models both of aortic [21] and cerebral aneurysms [8]. An immunohisto- chemical (IHC) study showed an iNOS expression in the aneurysm wall [17], while lack of iNOS was observed in the control arteries [5, 16]. Experimental in vitro studies suggested that the aneurysm development could be induced by an imbalance of VEGF, and its receptors (VEGFR1 and VEGFR2), through a mechanism involving endothelium nitric oxide (NO). Bussolati et al. demonstrated that the release of NO, VEGF stimulated, is inhibited by blocking VEGFR1. VEGFR1 via NO negatively regulates VEGFR2-mediated proliferation; therefore, the E. Maderna (&) Á B. Pollo Division of Neuropathology, Fondazione IRCCS Istituto Neurologico ‘‘C. Besta’’, Via Celoria 11, 20133 Milan, Italy e-mail: emaderna@istituto-besta.it E. Corsini Laboratory of Clinical Investigation, Fondazione IRCCS Istituto Neurologico ‘‘C. Besta’’, Milan, Italy A. Franzini Á S. Giombini Á G. Broggi Á C. L. Solero Á P. Ferroli Á G. Messina Á C. Marras Department of Neurosurgery, Fondazione IRCCS Istituto Neurologico ‘‘C. Besta’’, Milan, Italy 123 Neurol Sci (2010) 31:617–623 DOI 10.1007/s10072-010-0378-2