Vascular endothelial growth factor modulates systemic blood pressure changes in chronic intermittent hypoxia

ABSTRACT

Systemic arterial hypertension is a common association to chronic intermittent hypoxia. However, little is known about the molecular mechanisms that might mediate long term adaptive responses. Hypoxia inducible factor-la [HIF-1alpha] is upregulated in hypoxia and is linked to activation of several downstream proteins concerned with protective mechanisms. Most importantly, HIF-1-alpha is strongly linked to VEGF. However, whether the expression of both cytokines in chronic intermittent hypoxia could be specifically increased in renal and aortic tissue is unclear. VEGF is a potent vasodilator both in vitro and in vivo and systemic administration causes hypotensive effects in various animal models. Therefore, we sought to explore the gene expression pattern of HIF-1alpha and VEGF in rat kidney and aorta in response to chronic intermittent hypoxia, to investigate a possible role for VEGF in reducing blood pressure elevation in such cases. Adult male Wistar rats were randomly assigned intro CIH group exposed to one hr intermittent hypoxia [fractional inspiredFIO2 10%] for 5 day/week for 5 weeks. CIH-SU group [received SU54l6, a potent selective blocker for KDR-flk VEGF receptor, were subjected to the same hypoxia protocol as CIH group] and normoxic Nx control rats. Mean and systolic blood pressure were recorded at day 1,7,15,21,28 and 35 of hypoxic exposure and at the same time points in normoxic rats. At the end of the hypoxia protocol, the thoracic aortas from all groups were excised for studying the functional reactivity of vessels to phenylephrinePE induced contraction and Acetyl choline induced relaxation. Parts of excised aorta and rat renal tissue were also collected for RT PCR analysis of HIF-1alpha and VEGF mRNA. Chronic intermittent hypoxia caused a significant elevation in SBP and MAP in CIH and CIH-SU compared to normoxic controls. However a significant elevation in SBP and MAP was observed upon blocking VEGF receptors [CIH-SU] versus CIH group. A significant increase in aortic contractile responses together with reduced dilator responses was observed in chronically hypoxic rats compared to controls and a significant increase in aortic reactivity was observed in CIH-SU versus CIH. Detection of mRNA encoding for both HIF- 1alpha and VEGF by RT-PCR showed increased expression pattern for both cytokines which was evident in both renal and aortic tissues. Chronic intermittent hypoxia upregulates mRNA for both HIF-1alpha and VEGF in rat renal and aortic tissues. Blocking VEGF receptor action resulted in a significant elevation in arterial blood pressure. These data point to an important role for VEGF in preventing marked elevation in arterial pressure in chronic intermittent hypoxia