Different types of endothelial cells (EC) fulfill distinct tasks depending on 
their microenvironment. ECs are therefore difficult to genetically manipulate ex 
vivo for functional studies or gene therapy. We assessed lentiviral vectors 
(LVs) targeted to the EC surface marker CD105 for in vivo gene delivery. The 
mouse CD105-specific vector, mCD105-LV, transduced only CD105-positive cells in 
primary liver cell cultures. Upon systemic injection, strong reporter gene 
expression was detected in liver where mCD105-LV specifically transduced liver 
sinusoidal ECs (LSECs) but not Kupffer cells, which were mainly transduced by 
nontargeted LVs. Tumor ECs were specifically targeted upon intratumoral vector 
injection. Delivery of the erythropoietin gene with mCD105-LV resulted in 
substantially increased erythropoietin and hematocrit levels. The human 
CD105-specific vector (huCD105-LV) transduced exclusively human LSECs in mice 
transplanted with human liver ECs. Interestingly, when applied at higher dose 
and in absence of target cells in the liver, huCD105-LV transduced ECs of a 
human artery transplanted into the descending mouse aorta. The data demonstrate 
for the first time targeted gene delivery to specialized ECs upon systemic 
vector administration. This strategy offers novel options to better understand 
the physiological functions of ECs and to treat genetic diseases such as those 
affecting blood factors.