Table 1.

Vascular developmental defects secondary to mouse knockouts of ECM basement membrane matrix genes

Basement membrane component	Mouse knockout phenotype	Specific vascular phenotypic defects/comments	References
Laminin α4 chain (laminins 411, 421)	Mild, early postnatal lethality, newborns lethargic, pale, and icteric because of anemia and hemorrhage, survivors improve and have normal life span. Corneal angiogenesis assays with FGF-2 reveal early, more intense sprouting and grossly distorted vasculature with apparent hemorrhages and dilated vessels.	Diffuse hemorrhagic phenotype from smaller vessels, particularly associated with parturition. Discontinuous basement membrane in capillaries with reduction in collagen type IV and nidogen staining but normal levels of perlecan. Adult null mice correct these defects and have normal levels of collagen type IV, nidogen, perlecan, and express laminin-511 in capillary basement membranes.	Thyboll et al. 2001
Laminin α5 chain (laminins 511, 521)	Embryonic lethality between E13.5 and 16.5 with limb, neural tube, and placental defects. Placental labyrinth is malformed which primarily consists of interacting trophoblasts and endothelial cells with intervening basement membranes.	At E13.5-16.5, vessels were present in placental labryrinth, but the branching complexity was markedly reduced and vessel diameters were significantly increased. In normal embryos, trophoblasts and ECs are separated only by a basement membrane while in the mutant, only the ECs remained adherent to the basement membrane creating a cell-free space.	Miner et al. 1998
Fibronectin	Embryonic lethality after E8.5 with deficits in mesodermal development, particularly, notochord, somites, heart, as well as embryonic and extraembryonic vasculature. Combined knockout of alternatively spliced exons EIIIA and EIIIB show embryonic lethality (usually by E10.5) because of cardiovascular defects including failure of vascular remodeling and hemorrhage.	Cardiac and vascular defects vary with the genetic background (more severe defects in 129S4 vs. C57BL/6J background) as well as vessel location. In some cases, defects in EC-mesenchymal interactions (e.g., heart and aorta) may underlie the vascular morphogenic defects observed.	George et al. 1993; George et al. 1997; Astrof et al. 2007
Collagen type IV, α1/2 chain	Embryonic lethality between E10.5-E11.5; basement membrane laminin and nidogen-1 were detected underlying epithelia and endothelia, although showed weaker and more patchy staining. Areas of basement membrane discontinuity and fragmentation were apparent. Excessive amounts of maternal blood was present in the yolk sac cavity indicative of hemorrhage as was the presence of pericardial bleeding.	Impairment of the placental labyrinth was apparent as its thickness was reduced. At the time of embryonic death, dilated blood vessels were observed. Overall, vascular development appeared relatively normal with reduced capillary density sprouting into the neural layer. However, hemorrhage was observed in the heart and arteries with excessive yolk sac hemorrhage indicative of abnormalities in EC basement membrane contacts or stability.	Poschl et al. 2004
Perlecan	Embryonic lethality between E10-E12 as well as perinatally. The lethality occurs because of hemopericardium and cardiac arrest. There is no evidence for placental or vascular defects.	There are few apparent vascular developmental defects except for some microaneurysms that form in several tissues including lung, skin, and brain.	Costell et al. 1999
Nidogens 1 and 2	Viable mice, some seizure-like symptoms with loss of muscle control in hindlimbs, no discernable vascular phenotype. Overall, normal basement membrane assembly and Immunostaining of major basement membrane components.	Minimal to no vascular abnormalities, some structural abnormalities in basement membrane matrix of brain capillaries. Nidogen 2 appears to be expressed in higher amounts in EC basement membranes compared to other basement membranes. Probable compensation for both nidogens 1 and 2 following knockout.	Murshed et al. 2000; Dong et al. 2002; Miosge et al. 2002
Collagen type XVIII	Viable mice with eye abnormalities. Overall, vascular basement membranes and vascular development (with the exception of the eye) appear normal.	Delayed regression of hyaloid vessels in the vitreous; abnormal outgrowth of retinal vessels which may be secondary to the lack of regression and/or alterations in VEGF expression through changes in retinal hypoxia.	Fukai et al. 2002