Fig. 5. Summary of vascular phenotypes in the Alk1-deficient brain and depiction of underlying mechanisms.
a. Cerebrovascular phenotype of Alk1 and/or Itgb8 knock-out (KO) mice in the brain angiogenic foci. Homozygous Alk1 KO in the brain causes microscopic vascular dysplasia and macroscopic tangled vessels with arteriovenous (A-V) shunt [23]; heterozygous Alk1 KO or homozygous Itgb8 KO results in microscopic level of vascular dysplasia only. Heterozygous Alk1 KO plus Itgb8 homozygous deletion cause microscopic vascular dysplasia and hemorrhage. Alk12f/2f: exons 4–6 of both alleles of Alk1 gene are flanked by loxP sides and are deleted when Cre is expressed [23, 47]; Alk1 +/−: one allele of Alk1 is deleted [12]; Itgb8 2f/2f: exon 4 of both alleles of Itgb8 gene is flanked by loxP sides and is deleted when Cre is expressed [13]. b. Depiction of the mechanisms of Alk1 and Itgb8 deletion in the vascular malformation and hemorrhage. Normal cerebrovascularture is covered with mural cells (including pericytes and smooth muscle cells, top panel). Alk1 deletion in endothelial cells (reduced color intensity, bottom panel) reduces vascular mural cell coverage [46], and Itgb8 deletion in astrocytes (white color) results in abnormal sprouting [42]. Therefore, deletion of Itgb8 in the Alk1+/− brain enhances vascular dysplasia and hemorrhage.