Thus, the study highlights the vasculo-centric nature of PH causation and provides a convenient experimental platform to explore PH development without the confounding factors associated with parenchymal damage and independently of its different etiologies. While rescuing PH and its sequela remains a prime clinical goal, recent animal and clinical works have provided only limited evidence showing that targeting endothelial dysfunction can decrease intra-hepatic vascular Antipyrine resistance of liver vasculature in the cirrhotic liver, reduce portal pressure and result in improved liver function. Here we show that re-opening of SEC fenestrations via restoration of VEGF function fully reverses PH and its secondary manifestations. These finding suggest the deranged sinusoidal network as a possible therapeutic target and attempted decapillarization as a possible treatment modality. Remarkably, all intra- and extra-hepatic phenotypes were reversed with within 1 week of VEGF function restoration and mice became indistinguishable from controls. This was evident as follows: SEC fenestrations re-appeared. HSCs returned to a quiescent state as manifested in normal abundance in the peri-sinusoidal space. The amount of peri-sinusoidal collagen was reduced to an apparently close to normal level. As anticipated from the re-gain of normal sinusoidal structure and presumed return to a low resistance state, secondary complications also disappeared including resolution of ascites and venous collaterals and regression of splenomegaly. Here we harnessed a conditional transgenic system for liverspecific modulations of VEGF function to show that VEGF blockade leads to closure of SEC fenestration and to activation of peri-sinusoidal HSCs, acting in concert to induce sinusoidal capillarization. Enforced capillarization was sufficient to produce significant PH and its secondary complications in the absence of a detectable parenchymal damage. These results point out that liver fibrosis is not a mandatory requirement for PH development and highlight the key role of vascular perturbation as the proximal cause of PH. To our knowledge this is the first example of a PH animal model where loss-of-function of a single protein is sufficient to produce all hallmarks of the condition. Initially shown to function as an angiogenic factor, VEGF was subsequently shown to play different roles in the maintenance of adult vasculatures. Noteworthy, VEGF is Ginkgolide-A suggested to play a role in control of systemic blood pressure, as evidenced by induced hypertension in patients treated with the VEGF-neutralizing antibody Bevacizumab. Here, we uncovered yet another function of VEGF, namely, a requirement for ongoing VEGF signaling in order to keep SECs�� fenestrations in an open state. This was supported by closure of fenestrae upon inhibition of endogenous VEGF function and their re-opening upon restoration of VEGF function. We note that while ability of VEGF to form new fenestrae has been previously documented, a requirement for VEGF to maintain already formed fenestrae in mature SECs in vivo was not previously shown, as it necessitated the use of an on/off genetic switch system. These results are supported by a clinical trial findings that removing VEGF from the hepatic microvasculature in the setting of cirrhosis and portal hypertension has deletarious effect. The conditional VEGF switch system employed in this study provides several advantages over previously used methodologies of in vivo VEGF modulations. First, VEGF blockade takes place only in the relevant organ, thus circumventing systemic influences.