**5. Conclusions**

In conclusion, collaterals are unique among blood vessel types with regard to their formation, structure, function, prevailing shear stress, and susceptibility to variation in their extent caused primarily by differences in genetic background but also by environmental factors such as aging and risk factors. The present study provides our first look into how differences in collateral endothelial and smooth muscle cells may accommodate and contribute to these unique features. Moreover, the model/hypothesis shown in Figure 9, if correct, may begin to provide answers to two perplexing questions: Why do collaterals undergo rarefaction with aging and other vascular risk factors? They are chronically exposed to adverse hemodynamic conditions. How do they resist more extensive pruning away? Their mural cells have specializations or adaptations in structure and expression of factors that mitigate the effects of these conditions.

**Supplementary Materials:** Supplementary materials can be found at http://www.mdpi.com/1422-0067/20/15/ 3608/s1.

**Author Contributions:** H.Z. performed angiography, morphometry, in vivo experiments, immunostaining, expression analysis, animal husbandry, and statistical analysis; D.C. performed SEM and determined collateral tortuosity in perinatal mice; J.E.F. designed the experiments, data analysis, and figures and wrote the manuscript.

**Funding:** National Institutes of Health, National Institute of Neurological Diseases and Stroke (grant NS083633), and National Heart Lung and Blood Institute (grant HL111070).

**Acknowledgments:** We thank Kirk McNaughton for histological tissue sectioning and Katy Liu for assistance in preparation of the SEM samples.

**Conflicts of Interest:** The authors declare no conflict of interest.
